EA029614B1 - Pi3k protein kinase inhibitors, particularly pi3k delta and/or gamma inhibitors - Google Patents

Abstract

The present invention provides novel compounds (I) useful as PI3K protein kinase modulators, in particular as PI3K delta (δ) and/or gamma (γ) protein kinase modulators. The present invention also provides methods for preparing PI3K protein kinase modulators, pharmaceutical compositions containing said modulators, and methods of treatment, prevention and/or amelioration of PI3K kinase mediated diseases or disorders using said modulators.

Description

The invention relates to compounds suitable as modulators of ΡΙ3Κ protein kinase, in particular inhibitors of 3Κ δ and / or γ.

or its pharmaceutically acceptable salt, where

in each case, K ^{1 is} independently H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or halogen;

X is CH or Ν;

in each case, K is independently H, substituted or unsubstituted alkyl, or halogen;

K ^a and K ^{b are} independently selected from H and substituted or unsubstituted alkyl;

K ^c represents H, substituted or unsubstituted alkyl, -MH ₂ or halogen; in each case, n is independently selected from 0, 1, 2, 3, and 4; and

Su selected from

where

K ² and K ^{3 are} independently selected from H, halogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy (for example, alkyl substituted by fluorine, such as —CHP ₂ ), CM, —MH-8O ₂ —K ′, - ΝΟ ₂ , -MN ₂ , -MN-C (O) -K ', -C (O) -MN-K', -8O ₂ -K 'and -8O ₂ MK'K';

in each case, K 'is independently selected from H, hydroxy, halogen, carboxyl, cyano, nitro, oxo (= O), thio (= 8), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted quinil, substituted or

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unsubstituted cyclic acid, substituted or unsubstituted

K ⁴ is H or substituted or unsubstituted alkyl; provided that the connection is not selected from

3 - [[4-amino-3- (3-hydroxyphenyl) -1 // - pyrazolo [3,4-b /] pyrimidin-1-yl] methyl] -8methyl-2-phenyl-1 (2 //) isoquinolinone;

3 - [[4-amino-3- (3-hydroxyphenyl) -1 // - pyrazolo [3,4-b /] pyrimidin-1-yl] methyl] -8fluoro-2- (2-fluorophenyl) -1 ( 2I) -isoquinolinone;

3- [4-amino-1 - [[1,2-dihydro-8-methyl-2- (2-methylphenyl) -1 -oxo-3-isoquinolinyl] methyl] -1 / - pyrazolo [3,4- <U] pyrimidine-3 -yl] benzamide a;

3- [4-amino-1 - [[1,2-dihydro-8-methyl-2- (2-methylphenyl) -1-oxo-3-isoquinolinyl] methyl] -1H-pyrazolo [3,4- ] pyrimidine-3 -yl] -Ν-methylbenzamide;

3 - [[4-amino-3 - [4- (aminomethyl) phenyl] -1 // - pyrazole o [3,4-b /] pyrimidine-1 -yl] methyl] -8methyl-2- (2-methylphenyl ) -1 (2 //) - isoquinolinone;

3 - [[4-amino-3- (3-hydroxyphenyl) -17 U-pyrazolo [3,4- <U] pyrimidin-1 -yl] methyl] -2- (2chlorophenyl) -8-methyl-1 (2Я) isoquinolinone;

3 - [[4-amino-3- (3-hydroxyphenyl) -17U-pyrazolo [3,4- <7] pyrimidin-1-yl] methyl] -2- (2-ethyl phenyl) -8-methyl-1 ( 2H) -Ochainol inona;

3 - [[4-amino-3- (3-hydroxyphenyl) -1H-pyrazolo [3,4-b] pyrimidin-1-yl] methyl] -8methyl-2- [2- (1-methyl-ethyl) phenyl] - 1 (2H) -isoquinolinone;

3 - [[4-amino-3- (3-hydroxyphenyl) -1 // - pyrazolo [3,4-b /] pyrimidin-1-yl] methyl] -8fluoro-2- (2-methylphenyl) -1 ( 2D) -isoquinolinone;

3 - [[4-amino-3- (4-fluoro-3-hydroxyphenyl) -1H-pyrazolo [3,4-0] pyrimidine-1yl] methyl] -8-fluoro-2- (2-methylphenyl) -1 (2H) -isoquinolinone;

3 - [[4-amino-3 - (4-fluoro-3-hydroxyphenyl) -1H-pyrazolo [3,4-b /] pyrimidine-1 yl] methyl] -2- (2-methylphenyl) -1 (2I a) isoquinolinone;

3- [[4-amino-3- (4-chloro-3-hydroxyphenyl) -1 / Lpirazolo [3,4-g /] pyrimidin-1 -yl] methyl] 2- (2-methylphenyl) -1 ( 2 //) - isoquinolinone;

3 - [[4-amino-3- (3-hydroxyphenyl) -17U-pyrazolo [3,4-b /] pyrimidin-1 -yl] methyl] -2- (2methylphenyl) -1 (2I) -isoquinolinone;

3 - [[4-amino-3- (4-chlorophenyl) -17 U-pyrazolo [3,4-b /] pyrimidin-1-yl] methyl] -8-methyl-2 (2-methylphenyl) -1 (2H a) isoquinolinone;

3 - [[4-amino-3- (3,4-dimethoxyphenyl) -Sh-pyrazolo [3,4-b /] pyrimidin-1-yl] methyl] -2 (2-fluorophenyl) -8-methyl-1 (277) -isoquinolinone;

3 - [[4-amino-3- (4-hydroxyphenyl) -17U-pyrazolo [3,4-b /] pyrimidin-1-yl] methyl] -2- (2fluorophenyl) -8-methyl-1 (277) isoquinolinone;

3 - [[4-amino-3- (4-methoxyphenyl) -Sh-pyrazolo [3,4-b7] pyrimidin-1-yl] methyl] -8methyl-2- (2-methylphenyl) -1 (2H) - isoquinolinone;

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3 - [[4-amino-3 - (3,4-dimethoxyphenyl) -1 I-p irazolo [3,4-b /] pyrimidin-1 -yl] methyl] -8methyl-2- (2-methylphenyl) - 1 (2I) -isoquinolinone;

3 - [[4-amino-3- (3-fluorophenyl) -1J-pyrazolo [3,4-b /] pyrimidin-1-yl] methyl] -8-methyl-2 (2-methylphenyl) -1 (2H a) isoquinolinone;

3 - [[4-amino-3- (3-fluorophenyl) -1J-pyrazolo [3,4-b /] pyrimidin-1-yl] methyl] -2- (2fluorophenyl) -8-methyl-1 (2J) isoquinolinone;

3 - [[4-amino-3- (3-chlorophenyl) -1I-pyrazolo [3,4-b /] pyrimidin-1-yl] methyl] -8-methyl-2 (2-methylphenyl) -1 (2I a) isoquinolinone;

3 - [[4-amino-3 - (3-chlorophenyl) -1H-pyrazolo [3,4Y] pyrimidine-1 -yl] methyl] -2- (2fluorophenyl) -8-methyl-1 (2H) -isoquinolinone;

3 - [[4-amino-3- (4-hydroxyphenyl) -1J-pyrazolo [3,4-b /] pyrimidin-1-yl] methyl] -8methyl-2- (2-methylphenyl) -1 (2H) isoquinolinone;

3 - [[4-amino-3 - (3-fluoro-4-hydroxyphenyl) -1 H-pyrazolo [3,4-ά] pyrimidin-1 yl] methyl] -8-methyl-2- (2-methylphenyl) -1 (2H) -isoquinolinone;

3 - [[4-amino-3 - (3-fluoro-4-hydroxyphenyl) -1 H-pyrazolo [3,4-ά] pyrimidin-1 yl] methyl] -2- (2-fluorophenyl) -8-methyl -1 (2H) -isoquinolinone;

3 - [[4-amino-3- (4-fluorophenyl) -1J-pyrazolo [3,4-b /] pyrimidin-1-yl] methyl] -8-methyl-2 (2-methylphenyl) -1 (2H a) isoquinolinone;

3 - [[4-amino-3 - (3-chloro-4-hydroxyphenyl) -1H-pyrazolo [3,4-ά] pyrimidin-1 -yl] methyl] 2- (2-fluorophenyl) -8-methyl -1 (2H) -isoquinolinone;

3 - [[4-amino-3- (3-chloro-4-hydroxyphenyl) -1А-pyrazolo [3,4-b /] pyrimidin-1-yl] methyl]

8-methyl-2- (2-methylphenyl) -1 (2H) -isoquinolinone;

3 - [[4-amino-3- (4-chloro-3-hydroxyphenyl) -1J-pyrazolo [3,4-b /] pyrimidin-1-yl] methyl] 2- (2-fluorophenyl) -8-methyl -1 (2H) -isoquinolinone;

3 - [[4-amino-3- (4-chloro-3-hydroxyphenyl) -1А-pyrazolo [3,4-b /] pyrimidin-1-yl] methyl]

8-methyl-2- (2-methylphenyl) -1 (2H) -isoquinolinone;

3 - [[4-amino-3 - (4-chloro-3-methoxyphenyl) -1 I-p irazolo [3,4-b /] pyrimidine-1 -yl] methyl] 2- (2-fluorophenyl) -8 -methyl-1 (2H) -isoquinolinone;

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3 - [[4-amino-3 - (4-chloro-3-methoxyphenyl) -1 A-p irazolo [3,4-D] pyrimidin-1 -yl] methyl] 8-methyl-2- (2-methylphenyl ) -1 (2A) -isoquinolinone;

3 - [[4-amino-3 - (4-fluoro-3-hydroxyphenyl) -1A-pyrazolo [3,4-D] pyrimidin-1 yl] methyl] -8-methyl-2- (2-methylphenyl) -1 (2A) -isoquinolinone;

3 - [[4-amino-3- (3-hydroxyphenyl) -1A-pyrazolo [3,4-D] pyrimidin-1-yl] methyl] -2- (2fluorophenyl) -8-methyl-1 (2A) - isoquinolinone;

3 - [[4-amino-3 - (4-fluoro-3-hydroxyphenyl) -1A-pyrazolo [3,4-D] pyrimidine-1 yl] methyl] -2- (2-fluorophenyl) -8-methyl -1 (2A) -isoquinolinone;

3 - [[4-amino-3- (3-methoxyphenyl) -1A-pyrazolo [3,4-D] pyrimidin-1-yl] methyl] -8methyl-2- (2-methylphenyl) -1 (2A) - isoquinolinone;

3 - [[4-amino-3- (3-hydroxyphenyl) -1A-pyrazolo [3,4-D] pyrimidin-1-yl] methyl] -8methyl-2- (2-methylphenyl) -1 (2A) - isoquinolinone;

3 - [4-amino-1 - [[3,4-dihydro-5-methyl-3 - (2-methylphenyl) -4-oxo-2-quinazolinyl] methyl] 1A-pyrazolo [3,4-D] pyrimidine -3-yl] benzenesulfonamide;

3 - [4-amino-1 - [[3,4-dihydro-5-methyl-3 - (2-methylphenyl) -4-oxo-2-quinazolinyl] methyl] 1 A-pyrazolo [3,4-D] pyrimidine-3 -yl] benzonitrile;

2 - [[4-amino-3- (3-fluoro-4-methoxyphenyl) -1A-pyrazolo [3,4-D] pyrimidin-1-yl] methyl] 5-methyl-3- (2-methylphenyl) - 4 (FOR) -quinazolinone;

2- [[4-amino-3 - (4-fluoro-3-hydroxyphenyl) -1A-pyrazolo [3,4-D] pyrimidin-1 yl] methyl] -5-methyl-3- (2-methylphenyl) -4 (FOR) -quinazolinone;

2 - [[4-amino-3- (4-chloro-3-hydroxyphenyl) -1A-pyrazolo [3,4-D] pyrimidin-1-yl] methyl]

5-methyl-3- (2-methylphenyl) -4 (3a) -quinazolinone;

2 - [[4-amino-3- (4-methoxyphenyl) -1A-pyrazolo [3,4-D] pyrimidin-1-yl] methyl] -5methyl-3- (2-methylphenyl) -4 (3a) - quinazolinone;

2- [[4-amino-3- (3-fluoro-4-hydroxyphenyl) -1-A-pyrazolo [3,4-D] pyrimidin-1 yl] methyl] -5-methyl-3- (2-methylphenyl) -4 (FOR) -quinazolinone;

2- [[4-amino-3 - [4- (phenylmethoxy) phenyl] -1 -A-pyrazolo [3,4-D] pyrimidin-1 -yl] methyl] 5-methyl-3- (2-methylphenyl) - 4 (FOR) -quinazolinone;

2 - [[4-amino-3- (4-phenoxyphenyl) -1A-pyrazolo [3,4-D] pyrimidin-1-yl] methyl] -5methyl-3- (2-methylphenyl) -4 (3a) - quinazolinone;

2 - [[4-amino-3 - (3,4-d imethoxyphenyl) -1A-pyrazolo [3,4-D] pyrimidin-1 -yl] methyl] -5methyl-3- (2-methylphenyl) -4 (FOR) quinazolinone;

2 - [[4-amino-3- (3-hydroxyphenyl) -1A-pyrazolo [3,4-D] pyrimidin-1-yl] methyl] -3- (2chlorophenyl) -5-methyl-4 (3a) - quinazolinone; and

2 - [[4-amino-3- (3-hydroxyphenyl) -1A-pyrazolo [3,4-D] pyrimidin-1-yl] methyl] -5methyl-3- (2-methylphenyl) -4 (3a) - quinazolinone.

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In another embodiment, the present invention relates to a compound of formula (I)

or its pharmaceutically acceptable salt, where

in each case, K ^{1 is} independently H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or halogen;

X is CH or Ν;

in each case, K is independently H, substituted or unsubstituted alkyl, or halogen;

K ^a and K ^{b are} independently selected from H and substituted or unsubstituted alkyl;

K ^c is H, substituted or unsubstituted alkyl, -ΝΗ ₂ or halogen; in each case, η is independently selected from 0, 1, 2, 3, and 4; and

Su selected from

where

K ² and K ^{3 are} independently selected from H, halogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy (for example, alkyl substituted with fluorine, such as —CHP ₂ ), CH —N # 802 - ^, –ΝΟ2, - ΝΗ, -HN-C (O) -K ', -C (O) -HN-K', -8O2-K 'and -3θ2ΝΚ'ΝΚ';

in each case, K 'is independently selected from H, hydroxy, halogen, carboxyl, cyano, nitro, oxo (= O), thio (= 8), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted quinil, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclyl lkila, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heteroarylalkyl;

K ⁴ is H or substituted or unsubstituted alkyl; provided that

(ΐ) if K ^a and K ^b are H, X is CH, Su is

at ³

and K ³ is H, then K ^{2 is} not —OH, P, C1, —C (= O) HH ₂ or —OCH ₃ ;

(ϊϊ) if K ^a and K ^b are H, X is CH, Su is

to ³

and K ² is H, then K ^{3 is} not —CH ₂ —HH ₂ , C1, OH, or —OCH ₃ ;

(ϊϊϊ) if K ^a and K ^b are H, X is CH or Ν, Su is

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at ³

and K ² is OH, —O — CH3 or P, then K ^{3 is} not P, C1, OH or —O — CH3;

(ίν) if K ^a and K ^b are H, X is Ν, Su is

to ³

and K ³ is H, then K ^{2 is} not -OH or -δΟ _{2 2} ; and

(ν) if K ^a and K ^b are H, X is Ν, Su is

and K ² is H, then K ³ is —OCH ₃ , —O — CH ₂ —Ry, or —O-Ry.

Another embodiment is a compound having the formula (Ι-A) or (Ι-Β)

or its pharmaceutically acceptable salt,

where K ¹ , K, p, K ^a , K ^b , K ^with and Su such as defined above for the compounds of formula (I).

Another embodiment is a compound having the formula (Ι-Α1), (Ι-Α2), (IА3), (Ι-Α4), (Ι-Α5), (Ι-Β1), (Ι-Β2), ( Ι-Β3), (Ι-Β4) or (Ι-Β5)

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η ₂ ν

(Ι-Β4)

(Ι-Α4)

(Ι-Α5)

(Ι-Β5)

or its pharmaceutically acceptable salt,

where K ¹ , K, K ^a , K ^b , K ^with and Su such as defined above for the compounds of formula (I). Another embodiment is a compound having formula (II)

or its pharmaceutically acceptable salt,

where K ¹ , X, K, p, K ^with and Su such as defined above for the compounds of formula (I); and K ^a and K ^{b are} independently selected from H and substituted or unsubstituted alkyl, provided that if Su is

Another embodiment is a compound having the formula (P-1), (P-2), (P-3), (P-4) or (P-5)

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(P-5)

or its pharmaceutically acceptable salt,

where K ^a represents a substituted or unsubstituted alkyl; and

K ¹ , X, K, p, K ^c , K ² , K ³ and K ⁴ are as defined above for the compound of formula (I). Another embodiment is a compound having the formula (III)

or its pharmaceutically acceptable salt, where

K ^a is a substituted or unsubstituted alkyl; and

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K ¹ , K, X, η, K ^with and Su such as defined above for the compounds of formula (I).

Another embodiment is a compound having the formula (W-A) and (W-B)

or its pharmaceutically acceptable salt, where

K ^a is a substituted or unsubstituted alkyl; Su selected from

K ¹ , K, K ^c , X and Su are as defined above for the compound of formula (I).

The preferred embodiment is a compound having the formula (I), (ΙΑ), (Ι-Α1), (Ι-Α2), (Ι-Α3), (-Α4), (Ι-Α5), (Ι- Β), (Ι-Β1), (Ι-Β2), (Ι-Β3), (Ι-Β4), (Ι-Β5), (II), (-1), (ΙΙ-2), ( ΙΙ-3), (ΙΙ-4), (ΙΙ-5), (III), (ΙΙΙ-Α) or (ΙΙΙ-B), where Su is chosen from

Another preferred embodiment is a compound having the formula (I), (Ι-Α), (Ι-Α1), (Ι-Α2), (-Α3), (Ι-Α4), (Ι-Α5), (-Β), (Ι-Β1), (Ι-Β2), (Ι-Β3), (Ι-Β4), (Ι-Β5), (II), (ΙΙ-1), (ΙΙ-2 ), (II3), (ΙΙ-4), (ΙΙ-5), (III), (ΙΙΙ-A) or (ΙΙΙ-B), where K ^with is, P or ₂ .

Another preferred embodiment is a compound having the formula

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(I), (Ι-Α), (Ι-Α1), (Ι-Α2), (Ι-Α3), (Ι-Α4), (-Α5), (Ι-Β), (Ι-Β1 ), (Ι-Β2), (1-В3), (Ι-Β4), (Ι-Β5), (ΙΙ-1), (ΙΙ-2), (-3), (ΙΙ-4), (ΙΙ-5), (ΙΙΙ), (ΙΙΙ - a) or (ΙΙΙ-B) where R ^a is H, and R ^s represents H, methyl or ethyl.

Another preferred embodiment is a compound having the formula (Ι), (Ι-Α), (Ι-Α1), (Ι-Α2), (Ι-Α3), (Ι-Α4), (Ι-Α5), (-Β), (Ι-Β1), (Ι-Β2), (Ι-Β3), (Ι-Β4), (Ι-Β5), (), (ΙΙ-1), (ΙΙ-2 ), (3), (ΙΙ-4), (ΙΙ-5), (ΙΙΙ), (ΙΙΙ-A) or (ΙΙΙ-B), where K ^a is H, and K ^b is methyl.

Another preferred embodiment is a compound having the formula (Ι), (Ι-Α), (Ι-Α1), (Ι-Α2), (Ι-Α5), (Ι-Β), (Ι-Β1), (Ι-Β2), (Ι-Β5), (ΙΙ), (-1), (ΙΙ-2), (ΙΙ-3), (ΙΙ-4), (ΙΙ-5), (ΙΙΙ), (ΙΙΙ-A) or (ΙΙΙ-B), where K is H or halogen, preferably R.

Another preferred embodiment is a compound having the formula (Ι), (Ι-Α), (Ι-Α1), (Ι-Α2), (Ι-Α3), (Ι-Α4), (Ι-Β), (Ι-Β1), (Ι-Β2), (Ι-Β3), (РВ5), (ΙΙ), (ΙΙ-1), (ΙΙ-2), (ΙΙ-3), (-4), (ΙΙ5), (ΙΙΙ), (ΙΙΙ-Α) and (ΙΙΙ-B), where K ¹ is H or halogen, preferably R.

Another preferred embodiment is a compound having the formula (Ι), (Ι-Α), (Ι-Β), (ΙΙ), (ΙΙ-1), (ΙΙ-2), (ΙΙ-3), ( -4), (ΙΙ-5), (ΙΙΙ), (ΙΙΙ-Α) and (ΙΙΙ-B), where η is 0 or 1.

Another embodiment is a compound having the formula (), (ΙΙ), (ΙΙ-1), (ΙΙ-2), (ΙΙ-3), (ΙΙ-4), (-5), () , (ΙΙΙ-A) and (ΙΙΙ-B), where X is CH.

Another embodiment is a compound having the formula (), (ΙΙ), (ΙΙ-1), (ΙΙ-2), (ΙΙ-3), (ΙΙ-4), (-5), () , (ΙΙΙ-A) and (ΙΙΙ-B), where X is N.

The compounds of the present invention include compounds listed below (and in Table 1) and their pharmaceutically acceptable salts. The present invention should not be construed as limited to the specified specific compounds.

1. 3 - (1 - (4-amino-3 - (3-fluoro-4-isopropoxyphenyl) - 1H-pyrazolo [3.4 <1] pyrimidin-1 -yl) ethyl) -8-chloro-2-phenylisoquinoline -1 (2H) -one;

2. 3 - (1 - (4-amino-3 - (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3.4 <1] pyrimidin-1 -yl) ethyl) -8-fluoro-2- phenylisoquinolin-1 (2H) -one;

3. 2- (1 - (4-amino-3 - (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4ά] pyrimidin-1 -yl) ethyl) -5-fluoro-3-phenylquinazoline-4 (3N) -one;

4. 2- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4ά] pyrimidin-1 -yl) ethyl) -6-fluoro-3-phenylquinazoline-4 (3N) -one;

5. 3 - (1 - (4-amino-3 - (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4ά] pyrimidin-1 -yl) ethyl) -2-phenylisoquinolin-1 (2H) - he;

5 a. (+) - 3 - (1 - (4-amino-3 - (3-fluoro-4-isopropoxyphenyl) -1 H-pyrazolo [3,4ά] pyrimidin-1 -yl) ethyl) -2-phenylisoquinolin-1 ( 2H) -one;

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5b. (-) - 3 - (1 - (4-amino-3 - (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4ά] pyrimidin-1 -yl) ethyl) -2-phenylisoquinolin-1 (2H )-he;

6. 2- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3.4 <3] pyrimidin-1 -yl) ethyl) -3-phenylquinazoline-4 (3H )-he;

6a. (+) - 2- (1 - (4-amino-3 - (3-fluoro-4-isopropoxyphenyl) -1 H-pyrazolo [3,4ά] pyrimidine-1 -yl) ethyl) -3-phenylquinazoline-4 ( ZN) -one;

6b. (-) - 2- (1 - (4-amino-3 - (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3.4c!] Pyrimidin-1 -yl) ethyl) -3-phenylquinazolin-4 ( ZN) -one;

7. 3- (1- (4-amino-3- (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3.4-4] pyrimidine-1yl) ethyl) -2-phenylisoquinolin-1 (2H) - he;

7a. (+) - 3- (1- (4-amino-3- (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3,4ά] pyrimidin-1 -yl) ethyl) -2-phenylisoquinolin-1 (2H )-he;

7b. (-) - 3 - (1 - (4-amino-3 - (3-fluoro-4-hydroxyphenyl) -1 H-pyrazolo [3,4ά] pyrimidin-1 -yl) ethyl) -2-phenylisoquinolin-1 ( 2H) -one;

8. 2- (1 - (4-amino-3 - (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3.4-4] pyrimidin-1 yl) ethyl) -3-phenylquinazolin-4 (3N) -he;

9. N- (5- (4-amino-1- (1- (1-oxo-2-phenyl-1,2-dihydroisoquinolin-3 -yl) ethyl) -1H-pyrazolo [3,4- <1] pyrimidine 3-yl) -2-methoxyphenyl) methanesulfonamide;

9a. (+) - G4- (5- (4-amino-1- (1- (1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl) ethyl) 1H-pyrazolo [3,4-с1] pyrimidin-3-yl) -2-methoxyphenyl) methanesulfonamide;

9b. (-) - M- (5- (4-amino-1- (1- (1-oxo-2-phenyl-1,2-dihydroisoquinolin-3 -yl) ethyl) 1H-pyrazolo [3,4-c1] pyrimidin-3-yl) -2-methoxyphenyl) methanesulfonamide;

10. 2- (1- (4-amino-3- (4-methoxy-3-nitrophenyl) -1H-pyrazolo [3.4-4] pyrimidine-1yl) ethyl) -3-phenylquinazolin-4 (3N) - he;

11. 3 - (1 - (4-amino-3 - (3-amino-4-methoxyphenyl) -1 H-pyrazolo [3,4-ά] pyrimidine-1 yl) ethyl) -2-phenylisoquinolin-1 (2H )-he;

12. N- (5 - (4-amino-1 - (1 - (4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl) -1N-pyrazolo [3,4-4] pyrimidine-3 -yl) -2-methoxyphenyl) methanesulfonamide;

13. 2- (1 - (4-amino-3 - (3-fluoro-4-hydroxyphenyl) -1 H-pyrazolo [3,4-ά] pyrimidine-1 yl) ethyl) -6-fluoro-3-phenylquinazoline -4 (3N) -one;

14. 3 - (1 - (4-amino-Z - (3-fluoro-4-hydroxyphenyl) -1 H-pyrazolo [3,4-ά] pyrimidin-1 yl) ethyl) -8-chloro-2-phenylisoquinoline -1 (2H) -one;

14a. (+) - 3 - (1 - (4-amino-3 - (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3,4ά] pyrimidine-1 -yl) ethyl) -8-chloro-2- phenylisoquinolin-1 (2H) -one;

14b. (-) - 3 - (1 - (4-amino-3 - (3-fluoro-4-hydroxyphenyl) - 1H-pyrazolo [3,4ά] pyrimidine-1 -yl) ethyl) -8-chloro-2-phenylisoquinoline -1 (2H) -one;

15. 3 - (1 - (4-amino-3 - (3-fluoro-4-hydroxyphenyl) -1 H-pyrazolo [3,4-ά] pyrimidine-1 yl) ethyl) -8-fluoro-2-phenylisoquinoline -1 (2H) -one;

15a. (+) - 3- (1- (4-amino-3- (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3,4ά] pyrimidine-1 -yl) ethyl) -8-fluoro-2-phenylisoquinoline -1 (2H) -one;

15b. (-) - 3 - (1 - (4-amino-3 - (3-fluoro-4-hydroxyphenyl) - 1H-pyrazolo [3,4ά] pyrimidine-1 -yl) ethyl) -8-fluoro-2-phenylisoquinoline -1 (2H) -one;

16. 2- (1 - (4-amino-3 - (3-fluoro-4-hydroxyphenyl) -1 H-pyrazolo [3,4-ά] pyrimidine-1 yl) ethyl) -5-fluoro-3-phenylquinazoline -4 (3N) -one;

16a. (+) - 2- (1- (4-amino-3- (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3,4ά] pyrimidin-1 -yl) ethyl) -5-fluoro-3-phenylquinazoline -4 (3N) -one;

16b. (-) - 2- (1 - (4-amino-3 - (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3,4ά] pyrimidin-1 -yl) ethyl) -5-fluoro-3-phenylquinazoline -4 (3N) -one;

17. 3 - (1 - (4-amino-3 - (4- (difluoromethoxy) -3-fluorophenyl) -1H-pyrazolo [3,4ά] pyrimidine-1 -yl) ethyl) -8-chloro-2- phenylisoquinolin-1 (2H) -one;

17a. (+) - 3 - (1 - (4-amino-3 - (4- (difluoromethoxy) -3-fluorophenyl) -1H-pyrazolo [3,4ά] pyrimidin-1 -yl) ethyl) -8-chloro 2-phenylisoquinolin-1 (2H) -one;

- 13 029614

17b. (-) - 3 - (1 - (4-amino-3 - (4- (d iformethoxy) -3-fluorophenyl) -1H-pyrazolo [3.4 <1] pyrimidin-1 -yl) ethyl) -8 -chloro-2-phenylisoquinolin-1 (2H) -one;

18. 3 - (1 - (4-amino-3 - (4-methoxy-3-nitrophenyl) -1 H-pyrazolo [3,4- <1] pyrimidin-1 yl) ethyl) -8-chloro-2- phenylisoquinolin-1 (2H) -one;

19. 3 - (1 - (4-amino-3 - (3-amino-4-methoxyphenyl) -1 H-pyrazolo [3,4-ά] pyrimidine-1 yl) ethyl) -8-chloro-2-phenylisoquinoline -1 (2H) -one;

20. N- (5 - (4-amino-1 - (1 - (8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3 yl) ethyl) -1H-pyrazolo [3,4- <1] pyrimidin-3-yl) -2-methoxyphenyl) methanesulfonamide;

20a. (+) - M- (5- (4-amino-1 - (1 - (8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3 yl) ethyl) -1H-pyrazolo [3, 4- <1] pyrimidin-3-yl) -2-methoxyphenyl) methanesulfonamide;

20b. (-) - M- (5- (4-amino-1 - (1 - (8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3 yl) ethyl) -1H-pyrazolo [3, 4- <1] pyrimidin-3-yl) -2-methoxyphenyl) methanesulfonamide;

21. 3 - (1 - (4-amino-3 - (3-methyl-1 H-ind azol-6-yl) -1 H-pyrazolo [3,4-ά] pyrimidin-yl) ethyl) -8- chloro-2-phenylisoquinolin-1 (2H) -one;

21a. (+) - 3 - (1 - (4-amino-3 - (3-methyl-1H-indazol-6-yl) -1H-pyrazolo [3,4ά] pyrimidine- 1 -yl) ethyl) -8 -chloro-2-phenylisoquinolin-1 (2H) -one;

21b. (-) - 3 - (1 - (4-amino-3 - (3-methyl-1H-indazol-6-yl) -1H-pyrazolo [3,4ά] pyrimidine- 1 -yl) ethyl) -8 -chloro-2-phenylisoquinolin-1 (2H) -one;

22. 2- {1- [4-amino-3- (3-fluoro-4-isopropoxyphenyl) pyrazolo [3.4 h1] pyrimidine-1yl] propyl} -3-phenyl-3H-quinazolin-4-one;

and their pharmaceutically acceptable salts.

Table 1

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Illustrative compounds of the present invention also include those listed below (and in Table 2), and their pharmaceutically acceptable salts. The present invention again should not be construed as being limited to these specific compounds.

ΐ. 2- {1 - [4-amino-3 - (3-fluoro-4-isopropoxyphenyl) pyrazolo [3,4-b] pyrimidin-1 yl] ethyl} -6-fluoro-3- (3-fluorophenyl) -ZH - quinazolin-4-one;

π. 2- {1 - [4-amino-3 - (3-fluoro-4-isopropoxyphenyl) pyrazolo [3,4-с1] pyrimidin-1 yl] ethyl} -5-fluoro-3- (3-fluorophenyl) -ZH - quinazolin-4-one;

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ΐϋ. 2- {1 - [4-amino-3 - (3-fluoro-4-isopropoxyphenyl) pyrazolo [3,4-ά] pyrimidin-1 yl] ethyl) -3- (3-fluorophenyl) -ZH-quinazolin-4 -he;

ΐν. 2- {1 - [4-amino-3 - (3-fluoro-4-hydroxyphenyl) pyrazolo [3,4-ά] pyrimidin-1 yl] ethyl) -6-fluoro-3- (3-fluorophenyl) -ZH - quinazolin-4-one;

ν. 2- {1 - [4-amino-3 - (3-fluoro-4-hydroxyphenyl) pyrazolo [3,4-] pyrimidin-1 yl] ethyl) -5-fluoro-3- (3-fluorophenyl) -ZH - quinazolin-4-one;

νί. 2- {1 - [4-amino-3 - (3-fluoro-4-hydroxyphenyl) pyrazolo [3,4-] pyrimidin-1 yl] ethyl) -3- (3-fluorophenyl) -ZH-quinazolin-4 -he;

νίί. 3 - {1 - [4-amino-3 - (3-fluoro-4-isopropoxyphenyl) pyrazolo [3,4- <1] pyrimidin-1 yl] ethyl) -7-fluoro-2- (3-fluorophenyl) - 2H-isoquinolin-1-one;

νίπ. 3 - {1 - [4-amino-3 - (3-fluoro-4-isopropoxyphenyl) pyrazolo [3,4- <1] pyrimidin-1 yl] ethyl) -8-fluoro-2- (3-fluorophenyl) - 2H-isoquinolin-1-one;

ΐχ. 3 - {1 - [4-amino-3 - (3-fluoro-4-isopropoxyphenyl) pyrazolo [3,4- <1] pyrimidin-1 yl] ethyl) -7-fluoro-2-phenyl-2H-isoquinoline- 1 is one;

x 3 - {1 - [4-amino-3 - (3-fluoro-4-isopropoxyphenyl) pyrazolo [3,4- <1] pyrimidin-1 yl] ethyl) -2- (3-fluorophenyl) -2H-isoquinoline- 1 is one;

χΐ. 3 - {1 - [4-amino-Z - (3-fluoro-4-hydroxyphenyl) pyrazolo [3,4-ά] pyrimidin-1 yl] ethyl) -7-fluoro-2- (3-fluorophenyl) -2H isoquinolin-1;

chi 3 - {1 - [4-amino-Z - (3-fluoro-4-hydroxyphenyl) pyrazolo [3,4-ά] pyrimidin-1 yl] ethyl) -8-fluoro-2- (3-fluorophenyl) -2H isoquinolin-1-one;

χίπ. 3 - {1 - [4-amino-Z - (3-fluoro-4-hydroxyphenyl) pyrazolo [3,4-] pyrimidin-1 yl] ethyl) -7-fluoro-2-phenyl-2H-isoquinolin-1 -he;

χΐν. 3 - {1 - [4-amino-Z - (3-fluoro-4-hydroxyphenyl) pyrazolo [3,4-] pyrimidin-1 yl] ethyl) -2- (3-fluorophenyl) -2H-isoquinolin-1 -he;

and their pharmaceutically acceptable salts.

table 2

Etc Structure Πρ Structure Πρ Structure Πρ Structure ί Ρ And m ίί "Have And m XP ϋί ίν X but V but νί οΧ νίί νίϋ όάί ¹ , Ν. Μ χρ ΐχ 757 _Ν ζ ^{Ηζν /} λ- X , Ν. Μ ΧΡ χΐ 'ό5' X N <E χϋ χΐϋ 'five? χίν χρ

Another embodiment is a compound having the formula (a1), (a2), (c), (c2) or (d)

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Where

K ^a and K ^{b are} independently selected from H and substituted or unsubstituted alkyl, provided that at least one of K ^a and K ^{b is} not H;

Rd is a protective group; cd is a leaving group;

K ¹ , K and η are as defined above for the compound of formula (I).

According to another aspect, the present invention relates to a method for producing a compound of formula (I), (Ι-Α), (Ι-Α1), (Ι-Α2), (Ι-Α3), (Ι-Α4), (Ι-Α5) , (Ι-Β), (Ι-Β1), (Ι-Β2), (1-В3), (Ι-Β4), (Ι-Β5), (II), (ΙΙ-1), (II2) , (ΙΙ-3), (ΙΙ-4), (ΙΙ-5), (III), (ΙΙΙ-A) and (ΙΙΙ-B), including the conversion of a compound of formula (a1), (a2), (c) , (с2) or (ά) to a compound of formula (I), (Ι-Α), (Ι-Α1), (Ι-Α2), (-Α3), (Ι-Α4), (Ι-Α5) , (Ι-Β), (Ι-Β1), (Ι-Β2), (Ι-Β3), (Ι-Β4), (Ι-Β5), (II), (ΙΙ-1), (ΙΙ- 2), (ΙΙ-3), (ΙΙ-4), (ΙΙ-5), (III), (ΙΙΙ-A) and (ΙΙΙ-B), for example, as described below in schemes from 1 to 4.

Another embodiment of the present invention is a method of inhibiting ΡΙ3Κ (such as ΡΙ3Κ δ and / or γ) in a patient, comprising administering to the patient an effective amount of at least one compound according to the present invention, for example, compounds of formula (I), (-Α) , (Ι-Α1), (Ι-Α2), (Ι-Α3), (Ι-Α4), (Ι-Α5), (-Β), (Ι-Β1), (Ι-Β2), ( Ι-Β3), (Ι-Β4), (Ι-Β5), (II), (ΙΙ-1), (ΙΙ-2), (II3), (-4), (-5), ( Iii), (ΙΙΙ-a) and (ΙΙΙ-b), as defined above.

Another embodiment of the present invention is a method of treating an inflammatory, autoimmune or proliferative disease by modulating a protein kinase (such as ΡΙ3Κ δ and / or γ) kinase, which includes administering to a patient in need of this treatment an effective amount of at least one compound according to the present invention. In one embodiment, the compound according to the present invention inhibits the protein kinase ΡΙ3Κ δ. In another embodiment, the compound of the present invention inhibits инки 3 Κ δ and γ protein kinases.

Another embodiment of the present invention is a method of treating an inflammatory, autoimmune or proliferative disease by modulating a protein kinase (such as ΡΙ3Κ δ and / or γ) kinase, which includes administering to a patient in need of this treatment an effective amount of at least one compound according to the present invention in combinations (simultaneously or sequentially) with at least one other anti-inflammatory, immunomodulatory or anti-cancer agent. In one embodiment, the compound according to the present invention inhibits the protein kinase ΡΙ3Κ δ. In another embodiment, the compound of the present invention inhibits protein kinases δ and γ.

More specifically, the compounds of formula (I), (Ι-Α), (Ι-Α1), (Ι-Α2), (Ι-Α3), (Ι-Α4), (Ι-Α5), (Ι-Β) , (Ι-Β1), (IΒ2), (Ι-Β3), (Ι-Β4), (Ι-Β5), (II), (-1), (ΙΙ-2), (ΙΙ-3) , (ΙΙ-4), (ΙΙ-5), (III), (ΙΙΙ-Α) and (ΙΙΙ-Β) and their pharmaceutically acceptable salts can be administered to treat, prevent and / or alleviate diseases or disorders mediated by ΡΙ 3 and related protein kinases, in particular to alleviate diseases or disorders mediated by /3Κ δ and / or γ, including, but not limited to, inflammatory diseases or disorders, autoimmune diseases or disorders, cancer and other diseases liferativnye disease or disorder.

The compounds of the present invention are suitable for the treatment of various cancers, including, but not limited to, the following diseases:

carcinoma, including carcinomas of the bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gall bladder, ovaries, pancreas, stomach, cervix, thyroid, prostate gland, and skin, including squamous carcinoma;

hematopoietic tumors of lymphoid origin, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, lymphoma Hod-17 029614

Zhkina, non-Hodgkin's lymphoma, hairy cell lymphoma and Berkett's lymphoma;

hematopoietic tumors of myeloid origin, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia;

tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma,

glioma and schwannomas; and

other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigment, keratoacantoma, follicular thyroid cancer and Kaposi's sarcoma.

Due to the key role of protein kinases in regulating cell proliferation, generally, protein kinase inhibitors according to the present invention may act as reversible cytostatic agents that may be suitable for treating any disease process characterized by impaired cell proliferation, for example, benign prostatic hyperplasia, familial adenomatous polyposis, neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis after angioplasty or vascular surgery, the formation of hypertrophic scars, inflammatory bowel disease, transplant rejection, endotoxic shock and fungal infections.

The compounds of the present invention are modulators of apoptosis and are suitable for treating cancer (including, but not limited to, the types noted above), viral infections (including, but not limited to, herpes virus, pox virus, Epstein-Barr virus, Sindbis virus and adenovirus), preventing the development of AIDS in individuals infected with HIV, autoimmune diseases (including, but not limited to, systemic lupus erythematosus, autoimmune glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease and autoimm unny diabetes mellitus), neurodegenerative disorders (including but not limited to, Alzheimer's disease, dementia associated with AIDS, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarction, stroke and reperfusion injury, arrhythmias, atherosclerosis, liver diseases caused by toxin or associated with alcohol, hematological diseases (including but not limited to chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including, but not limited to, osteoporosis and arthritis), rhinosinusitis, aspirin-susceptible, cystic fibrosis, multiple sclerosis, kidney disease and cancer pains.

Compounds according to the present invention can modulate the level of cellular RNA and DNA synthesis. These agents are therefore suitable for the treatment of viral infections (including, but not limited to, HIV, human papillomavirus, herpes virus, pox virus, Epstein-Barr virus, Sindbis virus and adenovirus).

The compounds of the present invention are suitable for the chemical prevention of cancer. By chemical prevention is meant the suppression of the development of invasive cancer by blocking the initial mutagenic phenomenon or blocking the development of already damaged pre-tumor cells or suppressing the exacerbation of the tumor. The compounds described in this application are also suitable for suppressing angiogenesis and tumor metastasis. One embodiment of the invention is a method for suppressing angiogenesis or tumor metastasis in a patient in need thereof, comprising administering an effective amount of one or more compounds according to the present invention.

Another embodiment of the present invention is a method of treating a disease associated with the immune system (for example, an autoimmune disease), a disease or disorder that includes inflammation (for example, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, neuroinflammatory diseases, multiple sclerosis, uveitis and immune system disorders), cancer or another proliferative disease, disease or liver damage, disease or kidney disorders. The method includes the introduction of an effective amount of one or more compounds according to the present invention.

Examples of immune disorders include, but are not limited to, psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, rejection of allogeneic or xenogeneic transplant (organ, bone marrow, stem cells and other cells and tissues), graft-versus-host disease, lupus erythematosus, inflammatory disease, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (for example, Hashimoto thyroiditis and autoimmune thyroiditis), myasthenia (shuChNssha dga \ 35). autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic recurrent hepatitis, primary biliary cirrhosis, allergic conjunctivitis and atopic dermatitis.

In one embodiment, the compounds described in this application are suitable as immunosuppressive agents for preventing graft rejection, allogeneic rejection

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or xenogenic graft (organ, bone marrow, stem cells, other cells and tissues) and graft-versus-host disease. In other embodiments, graft rejection is caused by a tissue or organ transplant. In additional embodiments, the graft-versus-host disease is caused by bone marrow or stem cell transplantation. One implementation option is to prevent or reduce the risk of graft rejection, allogeneic or xenogenic graft rejection (organ, bone marrow, stem cells, other cells and tissues) or graft-versus-host disease, including the administration of an effective amount of one or more compounds according to the present invention.

The compounds of the present invention may also be administered in combination (simultaneously or sequentially) with known cancer treatment methods, such as radiotherapy, or with cytostatic or cytotoxic anti-cancer agents, such as agents that affect DNA, such as cisplatin or doxorubicin; topoisomerase inhibitors ΙΙ, such as etoposide; topoisomerase inhibitors Ι, such as CPT-11 or topotecan; agents acting on tubulin, such as paclitaxel, docetaxel, or natural or synthetic epothilone (for example, Ixabepilone); hormonal agents such as tamoxifen; thymidylate synthase inhibitors such as 5-fluorouracil; and antimetabolites, such as methotrexate, other tyrosine kinase inhibitors, such as Cutting and Ο8Ι-774; angiogenesis inhibitors; inhibitors of BOR; inhibitors of RBM; SOK inhibitors; inhibitors 8KS; c-ингибит inhibitors; Heg 1/2 inhibitors and monoclonal antibodies to growth factor receptors, such as Erbitux (EOP) and Herceptin (Heg2), other modulators of protein kinases, and combinations thereof.

The compounds of the present invention may also be administered in combination (simultaneously or sequentially) with one or more steroid anti-inflammatory drugs, nonsteroidal anti-inflammatory drugs (NSAIDs, “8ΑΙΌδ), or immunoselective anti-inflammatory derivatives (Ιιη805) and their combinations.

According to another aspect, the present invention relates to a pharmaceutical composition comprising one or more compounds according to the present invention (such as a compound of the formula (Ι), (Ι-Α), (Ι-Α1), (Ι-Α2), (Ι-Α3) , (Ι-Α4), (Ι-Α5), (Ι-Β), (Ι-Β1), (Ι-Β2), (Ι-Β3), (Ι-Β4), (Ι-Β5), ( ΙΙ), (ΙΙ-1), (ΙΙ-2), (ΙΙ-3), (ΙΙ-4), (ΙΙ-5), (ΙΙΙ), (ΙΙΙ-Α) or (-B)) and pharmaceutically acceptable carrier. The pharmaceutical composition may additionally contain one or more of the active ingredients mentioned above, such as, for example, additional steroidal anti-inflammatory drugs, non-steroidal anti-inflammatory drugs (NSAIDs, Ν8ΑΙΌκ), or immunoselective anti-inflammatory derivatives (ηιη805). anti-cancer agents and combinations thereof.

In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of one or more compounds of the formula (Ι), (Ι-Α), (Ι-Α1), (Ι-Α2), (-Α3), (-Α4), (Ι-Α5), (Ι-Β), (Ι-Β1), (Ι-Β2), (Ι-Β3), (Ι-Β4), (Ι-Β5), (), (ΙΙ-1 ), (ΙΙ-2), (ΙΙ-3), (ΙΙ-4), (ΙΙ-5), (), (ΙΙΙ-A) or (ΙΙΙ-B).

Another embodiment is a method of treating leukemia in a patient in need thereof, comprising administering a therapeutically effective amount of a compound according to the present invention. For example, the compounds of the present invention are effective in treating autoimmune disorders such as asthma, COPD, rheumatoid arthritis, psoriasis, lupus, and experimental autoimmune encephalomyelitis (EAE).

Another embodiment is a method of treating allergic rhinitis in a patient in need thereof, comprising administering a therapeutically effective amount of a compound according to the present invention.

Another embodiment is a method of treating leukemia in a patient in need thereof, comprising administering a therapeutically effective amount of a compound according to the present invention. For example, the compounds of the present invention are effective for the treatment of chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), acute myeloid leukemia (AML), multiple myeloma (MM), small cell lymphocytic lymphoma (MLL) and indolent non-Hodgkin lymphoma (I-NH ).

Detailed Description of the Invention

The following definitions should be used in this application unless otherwise indicated. In addition, most of the groups defined in the present description may be optionally substituted. The list of substituents in the definition is given as an example, and should not be construed as limiting the substituents defined in any part of the present description.

The term "alkyl", unless specifically stated otherwise, refers to a linear or branched hydrocarbon radical consisting solely of carbon and hydrogen atoms, not containing unsaturated sites, containing from one to eight carbon atoms, which is attached to the rest of the molecule through a simple bond for example, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl and 1,1-dimethylethyl (tert-butyl). The term "(Ό_ ₆ ) alkyl" refers to an alkyl group, as defined above, containing up to 6 carbon atoms.

The term "alkenyl", unless specifically indicated otherwise, refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond that can be linear or branched and contains from about 2 to about 10 carbon atoms, for example, ethenyl, 1- propenyl, 2- 19 029614

propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl.

The term "(C _2-6 ) alkenyl" refers to an alkenyl group, as defined above, containing up to 6 carbon atoms.

The term “alkynyl”, unless specifically indicated otherwise, refers to a linear or branched hydrocarbyl radical containing at least one carbon-carbon triple bond and from 2 to 12 carbon atoms (where radicals containing from 2 to 10 carbon atoms, are preferred according to the present invention), for example, to ethinyl, propynyl and butynil. The term "(C ₂₆ ) alkynyl" refers to an alkynyl group, as defined above, containing up to 6 carbon atoms.

The term "alkoxy", unless specifically stated otherwise, means an alkyl, cycloalkyl or cycloalkylalkyl group, such as defined herein, attached by an oxygen linker group to the rest of the molecule. The term "substituted alkoxy" refers to an alkoxy group in which the alkyl component is substituted (i.e., -O- (substituted alkyl)), where the term "substituted alkyl" has the same definition as "alkyl" ' above. For example, “alkoxy” refers to a —O-alkyl group containing from 1 to 8 carbon atoms, having a linear, branched, cyclic configuration, and combinations thereof, attached to the original structure through an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, and cyclohexyloxy.

The term "cycloalkyl", unless specifically stated otherwise, means a non-aromatic mono- or polycyclic ring system containing from about 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of polycyclic cycloalkyl groups include perhydronaphthyl, adamantyl and norbornyl groups, bridged cyclic groups and spirobicyclic groups, for example, spiro- (4,4) -non-2-yl. The term "(C _3-8 ) cycloalkyl" refers to a cycloalkyl group, as defined above, containing from 3 to 8 carbon atoms.

The term "cycloalkylalkyl", unless specifically stated otherwise, refers to a radical containing a cyclic ring containing from about 3 to 8 carbon atoms directly attached to an alkyl group, which, in turn, is attached to the main structure through any carbon atom an alkyl group to form a stable structure, such as cyclopropylmethyl, cyclobutylethyl and cyclopentylethyl.

The term "cycloalkenyl", unless specifically stated otherwise, refers to radicals containing a cyclic ring containing from about 3 to 8 carbon atoms and at least one carbon-carbon double bond, such as cyclopropyl, cyclobutenyl and cyclopentenyl. The term "cycloalkenylalkyl" refers to a cycloalkenyl group directly attached to an alkyl group, which, in turn, is attached to the main structure through any carbon atom of the alkyl group to form a stable structure.

The term "aryl", unless specifically stated otherwise, refers to aromatic radicals containing from 6 to 20 carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl and biphenyl.

The term "arylalkyl", unless specifically stated otherwise, refers to an aryl group, as defined above, directly associated with an alkyl group, such as defined above, for example, to -CH2C6H5 and -C2H5C6H5.

The term "heterocyclic ring", unless specifically stated otherwise, refers to a non-aromatic 3-15 membered ring radical containing carbon atoms and at least one heteroatom selected from nitrogen, phosphorus, oxygen and sulfur. For the purposes of the present invention, the heterocyclic ring radical may be a mono-, bi-, tri-, or tetracyclic ring system, which may include condensed, bridge, or spiro systems of rings, and nitrogen, phosphorus, carbon, oxygen, or sulfur atoms in the heterocyclic ring radical may be not necessarily oxidized to various degrees of oxidation. In addition, the nitrogen atom may not necessarily be quaternary. The heterocyclic ring radical can be attached to the main structure through any heteroatom or carbon atom to form a stable structure.

The term "heterocyclyl", unless specifically stated otherwise, refers to a heterocyclic ring radical as defined above. The heterocyclyl ring radical can be attached to the main structure through any heteroatom or carbon atom to form a stable structure.

The term "heterocyclylalkyl", unless specifically stated otherwise, refers to a heterocyclic ring radical, as defined above, directly linked to an alkyl group. The heterocyclylalkyl radical can be attached to the main structure through the carbon atom of the alkyl group to form a stable structure. Examples of these are: heterocyclic , piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxoio-20 029614

morpholinyl and 1,1-dioxothiomorpholinyl.

The term “heteroaryl”, unless specifically indicated otherwise, refers to a possibly substituted 5-14-membered aromatic ring containing one or more heteroatoms selected from, O, and 8 as ring atoms. Heteroaryl can be a mono-, bi- or tricyclic ring system. Examples of said “heterocyclic ring” and “heteroaryl” radicals include, but are not limited to, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazylly carcar. isoquinolyl, azetidinyl, acridinyl, benzodioxolyl, benzodioxanil, benzofuranyl, carbazolyl, cinnolyl, dioxolanyl, indolizinyl, naphthyridine, perhydroazepine, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, haphy; tetrahydrofibre, thiazolidine, isothiazolyl, hinuclidine, isothiazolidine, isoindolyl rfolinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, oxadiazolyl, chromanyl and isochromanil. Heteroaryl radical can be attached to the main structure through any heteroatom or carbon atom with the formation of a stable structure. The term “substituted heteroaryl” also includes ring systems substituted with one or more oxide (—O—) substituents, such as pyridinyl α-oxides.

The term “heteroarylalkyl”, unless specifically stated otherwise, refers to a heteroaryl ring radical, such as defined above, directly associated with an alkyl group. The heteroarylalkyl radical can be attached to the main structure through any carbon atom of the alkyl group to form a stable structure.

The term "cyclic ring" refers to a cyclic ring containing from 3 to 10 carbon atoms.

The term "substituted", unless specifically indicated otherwise, refers to substitution by any one of the following substituents or any combination thereof, where the substituents may be the same or different and are independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (= 0), thio (= 8), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, substituted or unsubstituted guanidine, -SOOK ^x, -C ( O) K ^x , -C (8) K ^x , -C (O) YK ^x K ^y , -C (O) OYK ^x K ^y , -ΝΗΊ®. -LYK ^x S0YK ^y K ² , -Y (K ^x ) 8OK ^y , -Y (K ^x ) 8O2K ^y , - (Ν-Ν (Ι%) ^ν ). -YK ^x S (O) OK ^y , -YK ^x K ^y , -YK ^x S (O) K ^y -, -YK ^x C (8) K ^y , -YK ^x C (8) YK ^y K ² , - 80ΝΗΊΤ-. -80; ΝΗΊΤ-. -OK ^x , -0К ^x С (0) YK ^y K ² , -OK ^x S (O) OK ^y -, -OС (O) K ^x , -OС (O) YK ^x K ^y , -K ^x OY ^y C (0) K ² , -K ^x OK ^y , -K ^x C (O) OK ^y , -K ^x C (0) YK ^y K ² , -K ^x C (O) K ^x , -K ^x OS ( O) K ^y , -8K ^x , -8OK ^x , -8O2K ^x and -0Ν02, where K ^x , K ^y and Κ ^ζ in each of the above groups can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl lkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring or substituted heterocyclylalkyl ring, or any two of the ^{X x} , K ^y and Κ ^ζ can be combined with a substitute. or an unsubstituted saturated or unsaturated 3-10 membered ring, which may optionally contain heteroatoms, which may be the same or different and selected from O,. "" (for example, measures R ^x may be hydrogen or C1 _-6 alkyl) or 8 substituent or combination of substituents, proposed in the present invention preferably lead to the formation of stable or permitted from the viewpoint of chemical compounds. The term "stable" as used in the present description refers to compounds or structure that do not substantially change when exposed to the conditions of their preparation, detection, and preferably isolation, purification, and inclusion in the pharmaceutical composition. Substituents in the above "substituted" groups cannot be further substituted. For example, if the substituent of the "substituted alkyl" represents a "substituted aryl", then the substituent of the "substituted aryl" cannot represent the "substituted alkenyl".

The term “halogen”, “halide” or alternatively halogen means fluorine, chlorine, bromine or iodine. The terms "haloalkyl", "haloalkenyl", "haloalkynyl" and "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxystructures, substituted with one or more halogen groups or combinations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include halogeno-

kylny and halogenoalkoxygroup, respectively, in which the halogen atom represents fluorine.

The term “protecting group” or “PC” refers to a substituent used to block or protect a specific functional group. Other functional groups in the compound may retain reactivity. For example, an “amino protecting group” is a substituent attached to an amino group that blocks or protects the amino functional group of a compound. Suitable amino-protecting groups include, but are not limited to, acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CB /), and 9-fluorenylmethylenoxycarbonyl (Rtos). Similarly, a “hydroxy protecting group” refers to a substituent on a hydroxy group that blocks or protects a hydroxy functional group. Suitable hydroxy protecting groups include, but are not limited to, acetyl and silyl. “Carboxy-protecting group” refers to a substituent on the carboxy group that blocks or protects the functional carboxy group. Suitable carboxy-protecting groups include, but are not limited to, —CH ₂ CH ₂ 8O ₂ Pb, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenylsulfenyl) ethyl, 2- (diphenylphosphino) ethyl and nitroethyl. For a general description of the protective groups and their applications, see T. A. Szepe, ProgosCus Shoers η Ogdats AtNszk. 1Appsu & 8oiz, №ν Wagk, 1991.

Certain compounds described in this application may contain one or more asymmetric centers and, thus, may have enantiomers, diastereomers and other stereoisomeric forms, which can be defined from the point of view of absolute stereochemistry as (K) - or (8) -. The chemicals, pharmaceutical compositions and methods of the present invention are intended to include all of the indicated possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Non-limiting examples of intermediate mixtures include mixtures of isomers in the ratio of 10:90, 13:87, 17:83, 20:80 or 22:78. Optically active (K) - and (8) -isomers can be obtained using chiral synthons or reagents or separated using conventional methods. If the compounds described in this application contain olefinic double bonds or other geometric asymmetry centers, and unless otherwise indicated, then the compounds are assumed to include E- and-geometric isomers.

"The leaving group (s) or atom" is any group (s) or atom, which (s) under the conditions of interaction, is split off from the original substance and thereby promotes interaction on a specific site. Suitable examples of these groups, unless specifically stated otherwise, include halogen atoms and mesyloxy, p-nitrobenzenesulfonyloxy and tosyloxy groups.

The present invention also further includes compounds that differ only in the presence of one or more isotopically enriched atoms, for example, in the case where hydrogen is replaced by deuterium or tritium, or the carbon atom is replaced by a carbon atom enriched to ¹³ ° C or ¹⁴ ° C.

Compounds according to the present invention can also include isotopes of one or more atoms that make up these compounds, contained in different ratios than natural ones. For example, compounds can be labeled with radioactive isotopes, such as, for example, tritium ( ³ H), iodine-125 ( ¹²⁵ 1) or carbon-14 ( ¹⁴ C). All isotopic variants of the compounds according to the present invention, which may be radioactive or non-radioactive, are included in the scope of the present invention.

Pharmaceutically acceptable salts forming part of the present invention include salts derived from inorganic bases such as Hz Ba, K, Ca, Md, Fe, Cu, Ζη, and Mi; salts of organic bases, such as Ν, Ν'-diacetyl diamine, glucamine, triethylamine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine and thiamine; chiral bases such as alkylphenylamine, glycinol and phenylglycinol; salts of naturally occurring amino acids, such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, ornithine, lysine, arginine and series; Quaternary ammonium salts of compounds of the present invention with alkyl halides, alkyl sulfates, such as Me1 and (Me) ₂ 8O ₄ , unnatural amino acids, such as Ό-isomers or substituted amino acids; guanidine; and substituted guanidine, where the substituents are selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substituted ammonium salts and aluminum salts. Salts may include acid addition salts, if possible, which may be sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulfonates, benzoates, salicylates, benzenesulfonates, ascorbates , glycerophosphates and ketoglutarates.

If physical properties, such as molecular weight, or chemical properties, such as chemical formulas, are described in this application using ranges, it is assumed that all combinations and subcombination of ranges and specific embodiments are included. The term “about”, if used in relation to a number or a numerical range, means that the number or the numerical range to which the indicated term refers is approximate to the experimental error (or statistical experimental error), and thus the number or The numeric range may differ from the indicated number or numerical range by a value from 1 to 15%. The term "containing" (and related terms such as "contain" or "contains" or "having" or "including") includes options for implementation, for example, one of the options for implementing any

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the composition of the substance, composition, method or process, etc., which "consist of" or "consist essentially of the described distinctive features.

The following abbreviations and terms have the indicated meanings: Ρ13-Κ = phosphoinositide-3-kinase; ΡΣ = phosphatidylinositol; AIDS = acquired immunodeficiency syndrome; HIV = human immunodeficiency virus; WE = methyl iodide; N / O = not determined.

The abbreviations used in this description have the meanings traditional in the field of chemistry and biology.

The term cell proliferation refers to the phenomenon in which cell number changes as a result of division. The term also covers cell growth, as a result of which the cell morphology changes (for example, an increase in size occurs), which corresponds to a proliferative signal.

The terms "co-administration", "introduced in combination with" and their grammatical equivalents, as used herein, encompass the administration of two or more agents to an animal, in which both agents and / or their metabolites are simultaneously present in the animal's body. Joint introduction includes the simultaneous introduction of the individual compositions, the introduction at different times in the composition of the individual compositions or the introduction of the composition, in which both agents are present.

The term “effective amount” or “therapeutically effective amount” refers to the amount of a compound described in this application that is sufficient for the intended effect, including, but not limited to, treatment of the disease, as defined below. A therapeutically effective amount may vary depending on the intended use (ίη νίΐΓΟ or ίη νίνο) or the subject and the disease condition being treated, such as the body weight and age of the subject, the severity of the disease condition, the route of administration, etc., and it can easy to identify experts in the field of technology. The term also refers to the dose that causes a specific response in cellular targets, for example, a decrease in platelet adhesion and / or cell migration. The specific dose depends on the particular compounds selected, the treatment regimen, the possible administration in combination with other compounds, the time of administration, the tissue into which the indicated dose is administered, and the physical delivery system in which the dose is administered.

According to the present description, “treatment”, “treatment” or “weakening” are used interchangeably. These terms refer to a method for achieving favorable or desired results, including, but not limited to, a therapeutic beneficial effect and / or a prophylactic beneficial effect. Under the therapeutic benefit action understand the elimination or weakening of the main disorders undergoing treatment. Also, the therapeutic beneficial effect is achieved by eliminating or alleviating one or more physiological symptoms associated with the underlying disorder, where improvement is observed in the patient, even if the subject has a major disturbance. For the prophylactic benefit action of the composition, it is possible to administer to a patient at risk of developing a particular disease, or to a patient who has reported one or more physiological symptoms of the disease, even if the diagnosis of said disease has not yet been made.

“Therapeutic effect” as used herein encompasses a therapeutic beneficial effect and / or a prophylactic beneficial effect, such as described above. Preventive effects include delaying or eliminating a disease or condition, delaying or eliminating the symptoms of a disease or condition, slowing, stopping or reversing the progression of a disease or condition, or any combination thereof.

The term “subject” or “patient” refers to an animal (for example, a dog, cat, horse, or pig), such as a mammal, for example, a human. The methods described in this application may be suitable for the treatment of humans and veterinary applications. In some embodiments, the patient is a mammal, and in some embodiments, the patient is a human.

'' Radiation therapy '' means exposing a patient using traditional methods and compositions known to practitioners, emitting agents, such as radionuclides, emitting alpha particles (eg, actinium and thorium radionuclides), emitting radiation with a low linear energy transfer (LET) (i.e., beta sources), agents that emit internal conversion electrons (such as strontium-89 and samarium, 153-) or high-energy radiation, including, without limitation, X-rays WCSS-rays, gamma rays and neutrons.

“Signal transduction” is the process by which stimulating or inhibiting signals are transferred into the cell to produce an intracellular response. A modulator of the signal transduction pathway refers to a compound that modulates the activity of one or more cellular proteins that belong to a specific signal transduction pathway. The modulator can enhance (agonist) or inhibit (antagonist) the activity of the signaling molecule.

The term "selective inhibition" or "selectively inhibit" used in relation to

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biologically active agent, refers to the ability of the agent to selectively reduce the target signaling activity compared with non-target signaling activity due to direct or indirect interaction with the target.

The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes, but is not limited to, any and all solvents, dispersing media, coatings, antibacterial and antifungal agents, isotonic agents and slowing agents, one or more suitable diluents, fillers, salts, disintegrating agents, binders, lubricants, glidants, wetting agents, controlled release matrices, dyes / flavorings, carriers, all omogatelnyh agents, buffers, stabilizers, solubility-enhancing agents, and combinations thereof. Except where any conventional medium or agent is incompatible with the active ingredient, it is intended to use them in the therapeutic compositions of the present invention. Additional active ingredients may also be included in the compositions.

In certain embodiments, one or more of the compounds described in this application specifically binds to a ΡΙ3 kinase or protein kinase selected from the group consisting of tTog, DNA-dependent protein kinase (registration number of the protein Reytey (ΡΡΑΝ) AAA79184), tyrosine kinase A1 (CAA52387) , Vsg-AB1, hemopoietic cell kinase (ΡΡΑΝ CP119695), ggs (ΡΡΑΝ CAA24495), receptor 2 vascular endothelial growth factor (ΡΡΛΡΡ ABB8219), epidermal growth factor receptor (ΡΡΑN AO43241), B4 receptor ERN ()N ЕР). stem cells (ΡΡ ΑN AAP22141), tyrosine protein kinase T1E-2 receptor (N 002858). ypk-like tyrosine kinase 3 (ΡΡΑN ΝΡ_004110), receptor for alpha platelet growth factor (ΡΡΑN ΝΡ_990080), KET (N CAA73131), and any other related protein kinases, as well as any of their functional mutants.

In other embodiments, the implementation of 1C ₅₀ compounds described in this application, with respect to ΡΙ 10α, ΡΙ 10β, ΡΙ 10γ or ΡΙ 10δ is less than about 1 μm, less than about 100 nm, less than about 50 nm, less than about 10 nm less than 1 nM or less than about 0.5 nM. In some embodiments, the implementation of the 1C _{50 of the} compound described herein with respect to tTog is less than about 1 μM, less than about 100 nM, less than about 50 nM, less than about 10 nM, less than 1 nM, or less than about 0, 5 nM In certain other embodiments, one or more compounds described herein have provided a dual-specific binding and may inhibit ΡΙ3 kinase (e.g., ΡΙ3 kinase Ι class) as well as protein kinase (e.g., minor) with a value of 1C _{50 of} less than about 1 μM, less than about 100 nM, less than about 50 nM, less than about 10 nM, less than 1 nM, or less than about 0.5 nM.

In additional embodiments of the compounds according to the present invention possess one or more functional characteristics disclosed in the present description. For example, one or more of the compounds described in this application specifically bind to ΡΙ3 kinase. In some embodiments, the implementation of 1C ₅₀ compounds described in this application, with respect to ΡΙ 10α, ΡΙ 10β, ΡΙ 10γ or ΡΙ 10δ is less than about 1 μm, less than about 100 nm, less than about 50 nm, less than about 10 nm , less than about 1 nM, less than about 0.5 nM, less than about 100 pM, or less than about 50 pM.

In other embodiments of the compounds according to the present invention selectively inhibit one or more members of the Ι type or Ι class of phosphatidylinositol-3-kinases (ΡΟ-kinases) with a value of Ι0 _{0 of} about 100 nM or less, about 50 nM or less, about 10 nM or less, about 5 nM or less, about 100 pM or less, about 10 pM or less, or about 1 pM or less in the инаη νίΐτο kinase study.

According to another aspect, it should be understood that an inhibitor that selectively inhibits one or more ΡI3 kinases of the type, or an inhibitor that selectively inhibits one or more signaling pathways mediated by the ΡI3 kinase of the в type, alternatively refers to a compound having a concentration of 50% inhibition of OC5O) with respect to this ΡI3-kinase зы type is 10 times lower, at least 20 times lower, at least 50 times lower, at least 100 times lower, at least 1000 times lower compared to Ι0 ₀ Inh inhibitors against other kinases Ι ΡI3-type.

According to the present description, the terms "double inhibitor 3I3 kinase δ / γ" and "double selective inhibitor ΡI3 kinase δ / γ" refer to a compound that more effectively inhibits the activity of оI3 kinase isoenzymes δ and γ compared to other isoenzymes of the ΡΙ3Κ family. The double inhibitor of ΡI3 kinase, δ / γ, thus, has a higher selectivity for ΡΙ3 kinase δ and γ compared to traditional 3Κ inhibitors, such as SAH-130, wortmannin and LU294002, which are non-selective inhibitors of ΡΙ3Κ.

Inhibition of ΡI3 kinase δ and γ can be beneficial in treating various conditions, such as conditions characterized by an inflammatory response, including, but not limited to, autoimmune diseases, allergic diseases and arthritis diseases. It is important to note,

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that inhibition of the function of the PB-kinase δ and γ probably does not affect biological functions, such as viability and reproductive ability.

“The inflammatory response” according to the present description is characterized by redness, burning, swelling, and pain (i.e., inflammation), and typically involves tissue damage or destruction. The inflammatory response is usually a localized protective response caused by tissue damage or destruction, which serves to destroy, dilute or separate (isolate) the agent that causes the damage and the damaged tissue. It should be noted that inflammatory responses are associated with an influx of leukocytes and / or chemotaxis of leukocytes (for example, neutrophils). Inflammatory responses can be caused by infection with pathogens and viruses, non-infectious causes, such as trauma or reperfusion after myocardial or stroke infarction, immune responses to foreign antigens and autoimmune diseases. Inflammatory responses that can be treated with the methods and compounds of the present invention encompass conditions associated with reactions of a specific defense system, as well as conditions associated with reactions of a non-specific defense system.

The treatment methods of the present invention include methods for alleviating conditions associated with the activation of inflammatory cells. '' Activation of inflammatory cells '' refers to the initiation of a proliferative cell response by a stimulus (including, but not limited to, cytokines, antigens or autoantibodies), the production of soluble mediators (including, but not limited to, cytokines, oxygen radicals, enzymes, prostanoids or vasoactive amines) or the expression of new mediators or an increased number of mediators (including, but not limited to, the major histocompatibility antigens or cell adhesion molecules) on the surface of inflammatory cells (in lyuchaya, but not limited to, monocytes, macrophages, T lymphocytes, B lymphocytes, granulocytes (polymorphonuclear leukocytes, including neutrophils, basophils, and eosinophils), mast cells, dendritic cells, Langerhans cells, and endothelial cells). Specialists in the art should understand that the activation of one of these phenotypes or their combination in these cells can influence the initiation, maintenance or enhancement of the inflammatory state.

"Autoimmune disease" according to the present description refers to a group of disorders in which tissue damage is associated with a humoral or cellular response to its own constituent components of the body.

“Graft rejection” according to the present description refers to any immune response directed to the transplanted tissue (including organs or cells (eg, bone marrow), characterized by loss of function of the transplanted and surrounding tissues, pain, swelling, leukocytosis and thrombocytopenia).

“Allergic disease” according to the present description refers to any symptoms, tissue damage or loss of tissue function caused by an allergy.

“Arthritic disease” according to the present description refers to any diseases that are characterized by inflammatory lesions of the joints that have different etiologies.

“Dermatitis” according to the present description refers to any of a large family of skin diseases characterized by inflammation of the skin, having a different etiology.

According to the above description, the “double selective inhibitor of IZ-kinase δ / γ” in general refers to a compound that more effectively inhibits the activity of the P! Zkinaza isoenzymes δ and γ in comparison with other isoenzymes of the IZK family. The relative effectiveness of the compounds as inhibitors of enzyme activity (or other biological activity) can be established by determining the concentration at which each compound inhibits activity to a predetermined level, and then comparing the results. As a rule, it is preferable to determine the concentration at which 50% inhibition of activity occurs in a biochemical study, i.e. concentration of 50% inhibition or "Κ ₅₀ ". Definition Κ. ' ₅₀ can be carried out using conventional methods known in the art. In general, Κ. ' ₅₀ can be determined by measuring the activity of this enzyme in the presence of various concentrations of the inhibitor tested. Then build a graph of dependence obtained in the experiment values of the activity of the enzyme on the concentration of the used inhibitor. The inhibitor concentration, which provides 50% enzyme activity (compared to activity in the absence of any inhibitors), is taken as the GS value. " Similarly, other inhibitory concentrations can be determined using an appropriate method for determining activity. For example, in some cases it may be desirable to determine the concentration of 90% inhibition, i.e. TC ₉₀ , etc.

Accordingly, it should be understood that, as an alternative, the double selective inhibitor of IZ-kinase δ / γ refers to a compound having a concentration of 50% inhibition (C ₅₀ ) in relation to IZ-kinase δ / γ, which is at least 10 times lower than at least 20 times lower or at least 3 times lower than значением. ' ₃₀ with respect to any or all of the other members of class I of the KIC family. In an alternative embodiment of the invention, the term dual selective inhibitor of IK-kinase δ / γ refers to a compound having Κ. ' ₅₀ in relation to R! W- 25 029614

δ / γ kinase, which is at least 30 times lower, at least 50 times lower, at least 100 times lower, at least 200 times lower or at least 500 times lower than Ιί ' . ' ₅₀ for any or all of the other members of class I of the family ΡΙ3Κ. The double selective inhibitor of RV kinase, δ / γ, is usually administered in an amount that selectively inhibits the activity of 3 kinase δ and γ, as described above.

In certain embodiments, the compounds according to the present invention inhibit the PB kinases δ and γ almost equally (~ 1: 1) or have a maximum ratio of activities to each isoenzyme of 1: 5, i.e. the compound according to the present invention has almost equal values Κ. ' ₅₀ for both RV kinase δ / γ enzymes, or the maximum difference between the two indicated values is 3-8 times.

The methods according to the present invention can be applied to cell populations of ίη νίνο or ex νίνο. 'Ιη νίνο' 'means in a living organism, for example, in an animal or human body or a subject's body. In this context, the methods of the present invention can be applied to an individual for therapy or prophylaxis. '' Ex νίνο '' or '' ίη νίΐΓο '' means '' outside a living individual ''. Examples of ex νίνο cell populations include ίη νίΐΓο cell cultures and biological samples, including, but not limited to, fluids or tissue samples obtained from individuals. These samples can be obtained using methods known in the art. Representative samples of biological fluids include blood, cerebrospinal fluid, urine, and saliva. Tissue samples include tumors and biopsies. In this context, the invention can be applied to various tasks, including therapeutic and experimental tasks. For example, the invention can be applied ex νίνο or ίη νίΐτο to determine the optimal regimen and / or dosage when administering a selective PK kinase inhibitor δ for a given indication, cell type, individual, and other parameters. The information obtained in this application can be used for experimental or diagnostic tasks or in the clinic to create treatment protocols ίη νίνο. Other ways to use ex νίνο for which the invention may be suitable are described below or will be apparent to those skilled in the art.

Pharmaceutical compositions

The invention provides a pharmaceutical composition comprising one or more compounds according to the present invention and one or more pharmaceutically acceptable carriers or excipients. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound according to the present invention. The pharmaceutical composition may contain one or more additional active agents, such as described in this application.

Pharmaceutical carriers and / or excipients can be selected from diluents, fillers, salts, disintegrating agents, binders, lubricants, glidants, humectants, controlled release matrices, dyes, flavoring agents, buffering agents, stabilizers, solubility enhancing agents, and their combinations.

In one embodiment, the pharmaceutical compositions described herein comprise from about 0.1 mg to about 1000 mg, for example, from about 1 mg to about 1000 mg, or from about 20 mg to about 800 mg, or from 50 mg to about 600 mg or from 50 mg to about 600 mg of one or more compounds according to the present invention, from 100 mg to about 400 mg of one or more compounds according to the present invention.

The pharmaceutical compositions of the present invention can be administered alone or in combination with one or more other active agents. If desired, the proposed compounds and the other (s) agent (s) can be mixed in one preparation, or both components can be incorporated into separate preparations for use in combination separately or simultaneously.

The compounds and pharmaceutical compositions of the present invention can be administered using any method that delivers the compounds to the site of action, such as oral, intranasal, topical (eg, transdermal), intraduodenal, parenteral (including intravenous, intraarterial, intramuscular, intravascular, intraperitoneal, or injection or infusion), intradermal, intramammary, intrathecal, intraocular, retrobulbar, intrapulmonary (for example, using medicinal aerosols) or subcutaneous (including the introduction of a depot for long-term release, for example, encapsulated spleen, brain or cornea), sublingual, anal, rectal, intravaginal, or by surgical implantation (eg, spleen capsule, brain or cornea) .

The compositions may be administered in solid, semi-solid, liquid or gaseous form, or in the form of a dried powder, for example, in a lyophilized form. The pharmaceutical compositions may be packaged in a convenient form for delivery, including, for example, solid dosage forms such as capsules, sachets, starch capsules, gelatin capsules, paper packaging, tablets, suppositories, granules, pills, molded lozenges, and chewable lozenges. The type of packaging generally depends on the desired mode of administration. Implantable formulations are also contemplated.

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sustained-release and transdermal formulations.

Method of treatment

The amount of compound administered depends on the subject (eg, mammal) undergoing treatment, the severity of the disorder or condition, the rate of administration, the precipitation of the compound, and the prescription of the prescribing physician. However, the effective dosage is in the range of from about 0.001 to about 100 mg / kg body weight per day, preferably from about 1 to about 35 mg / kg / day, and consists of one or more divided doses. For a 70 kg person, the amount is from about 0.05 to 7 g / day, preferably from about 0.05 to about 2.5 g / day. An effective amount of the compounds according to the present invention can be administered in one or more doses (for example, twice or three times a day).

The present invention also provides methods for using the compounds or pharmaceutical compositions of the present invention for treating disease states, including, but not limited to, diseases associated with dysfunction of one or more types of 3 kinases. A detailed description of the conditions and disorders mediated by the kinase activity of ΡΙ3Κ δ and / or γ is given, for example, in EO 2001/81346, application for US Patent No. 2005/043239, EO 2011/055215 and UO 2012/151525, the contents of each of which are included in the present application in its entirety by reference.

The treatment methods provided herein include administering to a subject a therapeutically effective amount of a compound according to the present invention. In one embodiment, the present invention provides a method for treating an inflammatory disorder, including autoimmune diseases, in a mammal. The method comprises administering to said mammal a therapeutically effective amount of a compound according to the present invention or a pharmaceutically acceptable salt thereof.

It should be understood that the treatment methods of the present invention are suitable for the fields of human medicine and veterinary medicine. Thus, the individual being treated can be a mammal, preferably a human or other animals. For veterinary purposes, individuals include, but are not limited to, farm animals, including cows, sheep, pigs, horses, and goats; domestic animals such as dogs and cats; exotic animals and / or animals kept in zoos; laboratory animals, including mice, rats, rabbits, guinea pigs and hamsters; and poultry such as chicken, turkey, duck and geese.

In some embodiments, a method of treating inflammatory or autoimmune diseases comprises administering to a subject (eg, a mammal) a therapeutically effective amount of one or more compounds of the present invention that selectively inhibit ΡΙ3Κ-δ and / or 3Κ-γ compared to all other ΡI3 kinases type Specified selective inhibition of ΡΙ3Κ-δ and / or ΡΙ3Κ-γ can be effective in the treatment of any diseases or conditions described in this application. For example, selective inhibition of ΡΙ3Κ-δ may suppress the inflammatory response associated with inflammatory diseases, autoimmune disease or diseases associated with an undesirable immune response, including, but not limited to, asthma, emphysema, allergies, dermatitis, rheumatoid arthritis, psoriasis, lupus erythematosus or graft-versus-host disease. Selective inhibition of ΡΙ3Κ-δ may additionally provide a reduction in the inflammatory or unwanted immune response in the absence of a concomitant decrease in the ability to reduce the bacterial, viral and / or fungal infection. Selective inhibition of ΡΙ3Κ-δ and ΡΙ3Κ-γ may be more effective in suppressing the immune response in a subject compared with the effect provided by separate administration of inhibitors that selectively inhibit ΡΙ3Κ-δ or ΡΙ3Κ-γ. According to one aspect, one or more of the proposed methods are effective in reducing the production of antibodies specific for antigens, w U1o about 2 times, 3 times, 4 times, 5 times, 7.5 times, 10 times, 25 times, 50 times, 100 times, 250 times, 500 times, 750 times, or about 1000 times or more. According to another aspect, one or more of the proposed methods are effective in reducing the production of Ι§Ο3 and / or Ι§ΟΜ specific for antigens, w wiuo about 2 times, 3 times, 4 times, 5 times, 7, 5 times, 10 times, 25 times, 50 times, 100 times, 250 times, 500 times, 750 times or about 1000 times or more.

In other embodiments, the present invention provides methods for using compounds or pharmaceutical compositions for treating respiratory diseases, including, but not limited to, diseases affecting the lobes of the lungs, pleural cavity, bronchioles, trachea, upper respiratory tract or nerves and muscles responsible for breath. For example, methods have been proposed for the treatment of obstructive pulmonary disease. Chronic obstructive pulmonary disease (COPD) is a broad term covering a group of respiratory diseases characterized by obstruction or restriction of the respiratory tract. The conditions included in this broad term are chronic bronchitis, emphysema and bronchiectasis.

In another embodiment, the compounds described herein are used to treat

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asthma. Also, the compounds or pharmaceutical compositions described herein can be used to treat endotoxemia and sepsis. In one embodiment, the compounds or pharmaceutical compositions described in this application are used to treat rheumatoid arthritis (RA). In another embodiment, the compounds or pharmaceutical compositions described herein are used for the treatment of contact or atopic dermatitis. Contact dermatitis includes irritant dermatitis, phototoxic dermatitis, allergic dermatitis, photoallergic dermatitis, contact urticaria, systemic contact dermatitis, etc. Irritant dermatitis can occur when a very large amount is applied to the skin, if the skin is sensitive to a specific substance. Atopic dermatitis, sometimes called eczema, is a type of dermatitis and is an atopic skin disorder.

The invention also relates to a method of treating a hyperproliferative disorder in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound according to the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to the treatment of cancer, such as acute myeloid leukemia, thymus, brain, lung cancer, squamous cell cancer, skin cancer, eyes, retinoblastoma, intraocular melanoma, oral cavity and oropharyngeal cancer, bladder cancer, gastrointestinal tract, stomach, pancreas, bladder, breast, cervix, head and neck, renal cell carcinoma. kidney, liver, ovarian, prostate cancer, colorectal cancer, esophagus, testicular cancer, gynecological cancers, thyroid cancer, CNS, PNS, AIDS-related cancer (for example, lymphoma or Kaposi's sarcoma) or caused by a virus. In some embodiments, the method relates to the treatment of a non-cancer-related hyperproliferative disorder, such as benign skin hyperplasia (eg, psoriasis), restenosis or prostatic hypertrophy (eg benign prostatic hypertrophy (BPH)).

The invention also relates to a method of treating diseases associated with vasculogenesis or angiogenesis in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound according to the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, the method is intended to treat a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema and scleroderma, diabetes, diabetic retinopathy , retrolental retinopathy, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian cancer, breast, lung, pancreas, prostate th prostate, colon and epidermoid cancer.

Patients that can be treated using the compounds of the present invention or their pharmaceutically acceptable salts in accordance with the methods of the present invention include, for example, patients diagnosed with psoriasis; restenosis; atherosclerosis; BPH; breast cancer, such as ductal carcinoma of the ductal breast tissue, medullary carcinomas, colloid carcinomas, tubular carcinomas, and inflammatory breast cancer; ovarian cancer, including ovarian epithelial tumors, such as ovarian adenocarcinoma and adenocarcinoma that has spread from the ovaries into the abdominal cavity; uterine cancer; cervical cancer such as cervical epithelial adenocarcinoma, including squamous cell carcinoma and adenocarcinoma; prostate cancer, such as prostate cancer, selected from the following diseases: adenocarcinoma or adenocarcinoma that has spread to the bone; pancreatic cancer such as epithelioid carcinoma of the ductal tissue of the pancreas and adenocarcinoma of the pancreatic ducts; bladder cancer such as transitional cell carcinoma of the bladder, urothelial carcinomas (transitional cell carcinomas), tumors of urothelial cells covering the bladder, squamous cell carcinomas, adenocarcinomas and small cell cancers; leukemia, such as acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myelogenous leukemia (AML), chronic myelogenous leukemia (MML), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CLL), multiple myeloma (MM) and myelodysplastic syndrome (MDS); bone cancer; lung cancer, such as non-small cell lung cancer (NSCLC), sub-species of which are squamous cell carcinomas, adenocarcinomas and undifferentiated large cell carcinomas, and small cell lung cancer; skin cancer, such as basal cell carcinoma, melanoma, squamous cell carcinoma, and actinic keratosis, which is a skin condition that sometimes develops into squamous carcinoma; ocular retinoblastoma; cutaneous or intraocular (ocular) melanoma; primary liver cancer (cancer that initially develops in the liver); kidney cancer; thyroid cancer such as papillary, follicular, medullary and anaplastic; AIDS-related lymphoma, such as diffuse B-cell large cell lymphoma, B-cell immunoblastic lymphoma, and small cell lymphoma from cells with unsplit nuclei; Kaposi's sarcoma; cancer caused by viruses, including hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatocellular carcinoma; lymphotropic virus

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human type Н (NTU-1) and adult T-cell leukemia / lymphoma; and human papillomavirus (HPV) and cervical cancer; cancers of the central nervous system (CNS), such as a primary brain tumor, including gliomas (astrocytoma, anaplastic astrocytoma or glioblastoma multiforme), oligodendrogliomas, ependymomas, meningiomas, lymphomas, schwannomas and medulloblastomas; cancers of the peripheral nervous system (PNS), such as acoustic neuromas and malignant peripheral nerve tumor membranes (MΡN§Τ) including neurofibromas and schwannomas, malignant fibrous tsitoma, malignant fibrous histiocytoma, malignant meningioma, malignant mesothelioma, and malignant mixed Mullerian tumor; oral and oropharyngeal cancer such as hypopharyngeal cancer, laryngeal cancer, nasopharyngeal cancer and oropharyngeal cancer; stomach cancer such as lymphomas, gastric stromal tumors, and carcinoid tumors; testicular cancer, such as germ cell tumors (CCTs), including seminoma and non-seminal tumors and stromal tumors of the gonads, including Leydig cell tumors and Sertoli cell tumors; cancer of the thymus gland, such as thymoma, thymus carcinoma, Hodgkin's disease, non-Hodgkin lymphoma, carcinoid syndromes, or carcinoid tumors; rectal cancer; and colon cancer.

According to another aspect, the present invention provides methods for dysfunction of leukocytes or dysfunction of osteoclasts. The method includes contacting a leukocyte or osteoclast with a quantity of a compound according to the present invention, which provides a dysfunction.

According to another aspect of the present invention, methods are provided for treating an ophthalmic disease by administering one or more of the proposed compounds or pharmaceutical compositions to the subject’s eye.

In some embodiments, the kinase is a lipid kinase or a protein kinase. In some embodiments, the kinase is selected from the group consisting of ΡΙ3 kinase, including various isoforms, such as ΡΙ3 kinase α, 3 kinase β, 3 kinase γ, 3 kinase δ; DNA ΡΚ; ttog; LY, UESRK, efrinovogo receptor B4 (ErryV4); ΤΕΚ receptor tyrosine kinase (HE2); PM8-like tyrosine kinase 3 (PbT-3); platelet growth factor receptor (TSRCA); KET; LTM; LTK; I8td-1; Nsk; 8gs; epidermal growth factor receptor (ESCA); ΚΓΓ; insulin receptor (EC) and YRK.

The invention further provides methods for modulating the activity of the ΡΙ3 kinase by contacting the ΡΙ3 kinase with a quantity of a compound according to the present invention, which is sufficient to modulate the activity of the ΡΙ3 kinase. Modulation may be the inhibition or activation of the ΡΙ3 kinase activity. In some embodiments, the invention provides methods for inhibiting the activity of the ΡΙ3 kinase by contacting the 3 kinase with a quantity of a compound that is sufficient to inhibit the activity of the ΡΙ3 kinase. In some embodiments, the invention provides methods for inhibiting the activity of the ΡΙ3 kinase. This inhibition can be carried out in solution, in a cell expressing one or more ΡΙ3 kinases, in a tissue containing a cell expressing one or more 3 kinases, or in an organism expressing one or more ΡΙ3 kinases. In some embodiments, the invention provides methods for inhibiting the activity of the зы3 kinase in an animal (including a mammal, such as a human) by contacting said animal with an amount of a compound according to the present invention that is sufficient to inhibit the activity of ΡΙ3 kinase in said animal.

In the following general procedure described in this application, ideas and methods for the preparation and use of a compound according to the present invention are proposed which are illustrative, but not restrictive. You can also assume an additional modification of the proposed methodology and additional new methods to ensure and implement the objectives of the invention. Accordingly, it should be understood that it is possible to propose other embodiments that are not beyond the nature and scope of the invention defined in the present description.

Illustrative compounds according to the present invention include compounds listed above in table. 1 and 2, and their pharmaceutically acceptable salts. The present invention should not be construed as limited to the indicated compounds.

General methods for producing compounds according to the present invention

Compounds according to the present invention can be obtained using methods (modified or without modifications), proposed in international patent publications \ UO 2008/127226, \\ 'About 2009/088986, \\' About 2011/055215 and \\ 'About 2012/151525 , the content of each of which is incorporated into this application by reference.

Unless otherwise indicated, it is assumed that the variables (for example, K, K ¹ , X, K ^a , K ^b , K ^c , n, and Su) used below in the formulas are the groups described above for the above formulas, such as formula (Ι). These methods can similarly be applied to other compounds having the formulas proposed above in the present description, with or without modifications.

Scheme 1. In this scheme, a method is proposed for preparing a compound of formula (Ι), where X is Ν, K is H, alkyl or halogen, Ρd is a protective group, and

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all other variables, such as K, K ¹ , K ² , K ³ , K ^a , K ^b , K ^c , X and η, are as described above for formula (I).

The compound of formula (a) can be reacted with a compound of formula (b) to form a compound of formula (c), wherein Pd is a suitable protecting group. In the compound of formula (c), you can remove the protective group to obtain the compounds of formula (s). It is possible to combine the compound of formula (s) with the compound of formula (e) under the Mitsunobu reaction conditions to produce the compound of formula (e), for example, in the presence of dialkyl azodicarboxylate and triarylphosphine.

It is possible to combine the compound of formula (e) with the compound of formula (ί) under Suzuki reaction conditions, for example, in the presence of a suitable base and palladium catalyst, such as Py (icrH) ₂ C1 ₂ -CH ₂ C1 ₂ , to obtain the target compound of formula ( I).

Alternatively, a combination of the compound of formula (i) can be carried out to obtain the desired compound of formula (I) under the Mitsunobu reaction conditions, for example, in the presence of dialkyl azodicarboxylate and triarylphosphine.

Scheme 2. In this scheme, a method is proposed for obtaining a compound of formula (I), where X is CH, K is H, alkyl or halogen, and all other variables, such as K ¹ , K ² , K ³ , K ^a , K ^ü , K ^c and η, are as described above for formula (I).

It is possible to combine the compound of formula (a1) with the compound of formula (d) to obtain the compound of formula (c1) under the Mitsunobu reaction conditions, for example, in the presence of dialkyl azodicarboxylate and triarylphosphine. It is possible to combine the compound of the formula (C1) with the compound of the formula (для) to obtain the target compound of the formula (I) under Suzuki reaction conditions, for example, in the presence of a suitable base and a palladium catalyst, such as Py (icpH) ₂ C1 ₂ -CH ₂ C1 ₂

Alternatively, you can combine the compounds of formula (A1) with the compound of the formula (s) to obtain the target compounds of formula (I) under the reaction conditions of Mitsunobu, for example,

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in the presence of dialkyl azodicarboxylate and triarylphosphine.

Scheme 3. In this scheme, a method is proposed for obtaining a compound of formula (I), where X is Ν, K is H, alkyl or halogen, O is OH or C1, Bd is a leaving group, and all other variables, such as K ¹ , K ² , K ³ , K ^a , K ^b , K ^c and n, are as described above for formula (I).

The compound of formula (a) can be reacted with a compound of formula (b1) to form a compound of formula (c2), where bd is a leaving group, such as a halogen group. The compound of formula (C2) can be alkylated using a compound of formula (e) in the presence of a suitable base to prepare a compound of formula (e) which can be combined with the compound of the formula (A) under Suzuki reaction conditions, for example, in the presence of a suitable base and palladium catalyst , such as Pj (0pp £) ₂ C1 ₂ -CH ₂ C1 ₂ , to obtain the target compound of formula (I).

Alternatively, the compound of formula (c2) can be alkylated using the compound of formula (i) in the presence of a suitable base to obtain the target compound of formula (I).

Scheme 4. In this scheme, a method is proposed for obtaining a compound of formula (I), where X is CH, K is H, alkyl or halogen, and all other variables, such as K ¹ , K ² , K ³ , K ^a , K ^b, K ^s and n, are as described above for formula (I).

The compound of formula (A1) can be converted to a compound of formula (A2). The compound of formula (A2) can be alkylated using a compound of formula (d) in the presence of a suitable base to form a compound of formula (C1) which can be combined with the compound

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of formula (ί) under Suzuki reaction conditions, for example, in the presence of a suitable base and a palladium catalyst, such as Pj (ipd) ₂ C1 ₂ -CH ₂ C1 ₂ , to obtain the target compound of formula ().

Alternatively, the compound of formula (a2) can be alkylated using the compound of formula (s) in the presence of a suitable base to obtain the target compound of formula (Ι).

Similar techniques with certain modifications known to those skilled in the art can be used to synthesize compounds of the formula (Ι), (Ι-Α), (Ι-Α1), (-Α2), (Ι-Α3), (Ι- Α4), (ΙΑ5), (Ι-Β), (Ι-Β1), (Ι-Β2), (Ι-Β3), (Ι-Β4), (Ι-Β5), (ΙΙ), (ΙΙ- 1), (ΙΙ-2), (ΙΙ-3), (ΙΙ-4), (ΙΙ-5), (ΙΙΙ), (ΙΙΙ-A) and (ΙΙΙ-B), where all variables are groups, described above for the above formulas, using suitable intermediates and reagents.

experimental part

In the examples and preparation examples provided below, the compounds according to the present invention and the methods for producing the above compounds are further illustrated and exemplified. It should be understood that the scope of the present invention is not limited in any way by the scope of the following examples and production examples. In the following examples, molecules having one chiral center, unless otherwise noted, exist as a racemic mixture. Molecules containing two or more chiral centers, unless otherwise noted, exist as a racemic mixture of diastereomers. The individual enantiomers / diastereomers can be obtained using methods known to those skilled in the art.

According to the present description, superscript 1 refers to the international patent application PCT / ΙΒ 2010/002804 (^ O 2011/055215), and superscript index 2 refers to the international patent application PCT / I8 2012/036594 (TH 2012/151525).

Table 3. Intermediate compounds

C1 ίιΎ to/ Prom L® he [. one C1 ⁰ Αι AA kccx / C1 Prom. 2 ΑΑΌ he Industrial connection 3 AAA C1 Industrial connection four AAA and..· /BUT C1 Industrial connection five R Λ _Ν Χ) _G A® gA-- ° ABOUT- THAT BODY CATO, / ss. _n " C1 C1 C1 /BUT Industrial connection 6 C1 Industrial connection eight Industrial connection 9 C1 Industrial connection 7 Industrial connection ten Lk ΛΑΌ Current Current sd -Hell to m with/ C1 Industrial connection eleven ? 9 η ₂ ν poison C1 C1 Industrial connection 15 Industrial connection 12 ι X ^m η ₂ ν Industrial connection 14 Industrial connection 13

Intermediate compound 1. 8-Chloro-3- (1-hydroxyethyl) -2-phenylisoquinolin-1 (2H) -one K 3- (1-aminoethyl) -8-chloro-2-phenylisoquinolin-1 (2H) -one ( 7.0 g, 23.46 mmol) was added HCl (7.13

ml) and cooled to 0 ° C. A solution of sodium nitrite (4.85 g, 70.39 mmol) in water (135 ml) was added to the mixture and stirred at RT for 30 minutes. The reaction mixture was heated to 135 ° C for 4 hours. The reaction mixture was made alkaline with a saturated solution of sodium bicarbonate, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography using ethyl acetate: petroleum ether to obtain the target compound as a brown solid (3.70 g, 53%), which was used without purification in the next step.

Intermediate 2. 8-Chloro-3- (1-chloroethyl) -2-phenylisoquinolin-1 (2H) -one B is a cooled solution of intermediate 1 (0.500 g, 1.67 mmol) in dichloromethane (10 ml)

and triethylamine (0.50 ml, 5.01 mmol) was added methanesulfonyl chloride (0.30 ml, 3.34 mmol), stirred at room temperature for 24 hours. The reaction was quenched with water, extracted with dichloromethane, dried over sodium sulfate and concentrated . The crude product was purified by column chromatography using ethyl acetate: petroleum ether to obtain the target compound as a brown solid (0.200 g, 37%). Mass: 318.0 (M +).

Intermediate compound 3. 8-Fluoro-3- (1-hydroxyethyl) -2-phenylisoquinolin-1 (2H) -one. The title compound was obtained as a yellow solid (0.940 g, 100%).

using a method similar to that described for the preparation of intermediate 1, from 3- (1-amino-ethyl) -8-fluoro-2-phenylisoquinolin-1 (2H) -one (0.880 g, 3.11 mmol), 6N. HC1 (12 ml), sodium nitrite

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(0.335 g, 4.86 mmol) and used without purification in the next stage.

Intermediate compound 4. 3- (1-Chloroethyl) -8-fluoro-2-phenylisoquinoline-1 (2H) -one

The title compound as a yellow solid (0.586 g, 58%) was obtained using a method similar to that described for preparing intermediate 2, from intermediate 3 (0.940 g, 3.31 mmol), dichloromethane (20 ml ) and triethylamine (1.30 ml, 9.95 mmol), methanesulfonyl chloride (0.51 ml, 6.63 mmol) and used without purification in the next step.

Intermediate compound 5. 2- (2-Chlorpropanamido) -6-fluoro-bphenylbenzamide

To a solution of 2-amino-6-fluoro-bphenylbenzamide (1.50 g, 6.51 mmol) in dichloromethane (20 ml) and di-isopropylethylamine (1.00 g, 7.81 mmol), cooled to 0 ° C, drop by drop 2-chloropropionyl chloride (0.75 ml, 7.81 mmol) was added. After 1 h, the reaction was quenched with water, the mixture was extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution, brine, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography using ethyl acetate: petroleum ether to obtain the target compound as an off-white solid (1.60 g, 77%). ¹ H NMR (δ ppm, COCl _3. 400 MHz): 11.86 (8, 1H), 8.45 (ά, 1 = 8.4 Hz, 1H), 8.37 (, 1 = 12.8 Hz, 1H), 7.63 (t, 2H), 7.49-7.38 (t, 3H), 7.23 (1, 1 = 7.5 Hz, 1H), 6.97 (, 1 = 11.7, 8.4 Hz, 1H), 4.53 (d, 1 = 7.0 Hz, 1H), 1.81 (ά, 1 = 7.0 Hz, 3H).

Intermediate compound 6. 2- (1-Chloroethyl) -5-fluoro-3-phenylquinazolin-4 (3H) -one

POC1 ₃ (13.3 ml) was added to intermediate 5 (1.60 g, 4.98 mmol) and heated to 125 ° C for 12 hours. The reaction was quenched in ice, the mixture was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate . The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by column chromatography using ethyl acetate: petroleum ether to obtain the target compound as a brown solid (0.85 g, 57%). Mass: 303.0 (M +).

Intermediate compound 7. 2- (2-Chlorpropanamido) -6-fluoro-bphenylbenzamide

The title compound as a brown solid (2.60 g, 80%) was obtained using a method similar to that described for intermediate 5, from 2-amino-5-fluoro-bphenyl benzamide (2.50 g, 10, 07 mmol), dichloromethane (20 ml), α-diisopropylethylamine (2.10 g, 12.08 mmol) and 2-chloropropionyl chloride (1.17 ml, 12.08 mmol). 'H NMR (δ ppm, COCl ₃ , 400 MHz): 11.23 (8, 1H), 8.45 (άά, 1 = 9.2, 5.1 Hz, 1H), 7.96 (8, 1H ), 7.66 (t, 2H), 7.43 (t, 2H), 7.35 (άά, 1 = 12.0, 9.1 Hz, 1H), 7.23 (t, 2H), 4 , 51 (d, 1 = 7.0 Hz, 1H), 1.81 (ά, 1 = 7.0 Hz, 3H).

Intermediate compound 8. 2- (1-Chloroethyl) -6-fluoro-3-phenylquinazolin-4 (3H) -one

The title compound as a yellow solid (0.398 g, 35%) was obtained using a method similar to that described for preparing intermediate 6, from intermediate 7 (1.20 g, 3.74 mmol) and POC1 ₃ (10 ml). Mass: 303.1 (M +).

Intermediate 9. 3- (1-Chloroethyl) -2-phenylisoquinolin-1 (2H) -one

The title compound as a yellow solid (1.00 g, 58%) was obtained using a method similar to that described for preparing intermediate 1, from 3- (1-amino-ethyl) -2-phenylisoquinolin-1 (2H) - it (1.60 g, 6.05 mmol), 6n. HC1 (19.2 ml), sodium nitrite (0.650 g, 9.44 mmol). Mass: 284.2 (M +).

Intermediate compound 10. 2- (2-Chlorpropanamido) -phenylbenzamcd

The title compound as a yellow solid (2.10 g, 98%) was obtained using a method similar to that described for the preparation of intermediate 5, from 2-amino-bphenylbenzamide (1.50 g, 7.06 mmol), dichloromethane (15 ml), α-diisopropylethylamine (1.09 g, 8.48 mmol) and 2-chloropropionyl chloride (1.76 g, 8.48 mmol) and used without purification in the next step.

Intermediate compound 11. 2- (1-Chloroethyl) -3-phenyl-cnazolin-4 (3H) -one

The title compound as a whitish solid (1.00 g, 53%) was obtained using a method similar to that described for intermediate 6, from intermediate 10 (2.00 g, 6.60 mmol) and POC1 ₃ (16 ml). Mass: 284.9 (M +).

Intermediate compound 12. 3- (1- (4-Amino-3-iodo-1H-pyrazolo [3,4 ^] pyrimidin-1-yl) ethyl) -2-phenylisoquinoline-1 (2H) -one

To a solution of 3-iodine-1H-pyrazolo [3,4 ^] pyrimidin-4-amine ¹ (0.45 g, 1.76 mmol) in DMF (7.5 ml) was added potassium carbonate (0.48 g, 3 , 52 mmol) and stirred at room temperature for 1 hour. The reaction mixture was cooled to 0 ° C, intermediate 9 was added (0.65 g, 2.29 mmol) and stirred at room temperature for 12 hours. The reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography using ethyl acetate: petroleum ether to afford the title compound as a brown solid (0.046 g, 39%). Mass: 508.9 (M +).

Intermediate compound 13. 3- (1- (4-Amino-3-iodo-1H-pyrazolo [4,3 ^] pyrimidin-1-yl) ethyl) -8 chloro-2-phenylisoquinolin-1 (2H) -one

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The title compound as a brown solid (0.500 g, 53%) was obtained using a method similar to that described for preparing intermediate 12, from 3-iodo-1H-pyrazolo [4,3-b] pyrimidine-4 α-amine (0.45 g, 1.72 mmol), potassium carbonate (0.476 g, 3.44 mmol), DMF (7.3 ml) and intermediate 2 (0.713 g, 2.24 mmol) and used without purification in the next stage.

Intermediate compound 14. 2- (2-Chlorobutanamido) -M-phenylbenzamide

To a solution of 2-amino-M-phenylbenzamide (2.0 g, 9.42 mmol) in dichloromethane (40 ml) was added 2-chlorobutyric acid (1.26 g, 10.36 mmol), triethylamine (14.81 ml, 101 mmol ) and 4-dimethylaminopyridine (0.230 g, 1.88 mmol), then dicyclohexylcarbodiimide (3.88 g, 18.84 mmol). After keeping for 12 hours at room temperature, the precipitated solid was filtered off and the solution was concentrated. The crude product was purified by column chromatography using ethyl acetate: petroleum ether to obtain the target compound as an off-white solid (2.00 g, 67%). ^! H NMR (δ ppm, DMSO- ₆ , 400 MHz): 11.06 (s, 1H), 10.41 (s, 1H), 8.21 (b, 1 = 8.2 Hz, 1H), 7 , 83 (b, 1 = 7.8 Hz, 1H), 7.69 (t, 2H), 7.57 (t, 1H), 7.37 (!, 1 = 7.9 Hz, 2H), 7 , 30 (!, 1 = 7.6 Hz, 1H), 7.14 (!, 1 = 7.4 Hz, 1H), 4.64 (bb, 1 = 7.3, 5.6 Hz, 1H) , 2.07-1.86 (t, 2H), 0.98 (b, 1 = 7.3 Hz, 3H).

Intermediate compound 15. 2- (1-Chloropropyl) -3-phenylquinazolin-4 (3H) -one

To intermediate 14 (1.00 g, 3.15 mmol) was added CΡΟΡΟ1 (15 ml) and heated to 125 ° C for 48 h. The reaction was quenched in ice, the mixture was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by column chromatography using ethyl acetate: petroleum ether to obtain the target compound as a yellow solid (0.200 g, 21%). ^! H NMR (δ ppm, DMSO-b ₆ , 400 MHz): 8.16 (bb, 1 = 7.9, 1.0 Hz, 1H), 7.92 (b!, 1 = 8.3, 1, 5 Hz, 1H), 7.78 b, 1 = 7.7 Hz, 1H), 7.62-7.44 (t, 6H), 4.64 (bb, 1 = 7.6, 6.7 Hz , 1H), 2.38 (t, 1H), 2.09 (t, 1H), 0.91 (b, 1 = 7.3 Hz, 3H).

Example 1

3- (1- (4-Amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-b] pyrimidin-1-yl) ethyl) -8-chloro-2phenylisoquinolin-1 (2H )-he

3- (1 - (4-Amino-3 - (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo | 3.4δ | pyrimidin-1-yl) ethyl) -8- \ ent-2phenylisoquinolin-1 (2H) - he

To a solution of 3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-b] pyrimidine-4-amine ¹ (0.091 g, 0.314 mmol) in DMF (2 ml) was added potassium carbonate (0.087 g, 0.628 mmol) and stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0 ° C, intermediate 2 was added (0.200 g, 0.628 mmol) and stirred at 90 ° C for 3 hours. The reaction was quenched with water and the precipitate was filtered off and dried in vacuo. The crude product was purified by column chromatography using ethyl acetate: petroleum ether to afford the title compound as an off-white solid (0.030 g, 17%). T _pl : 164-166 ° C. Mass: 569.7 (M +).

Example 2

3- (1- (4-Amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-b] pyrimidin-1-yl) ethyl) -8-fluoro-2phenylisoquinolin-1 (2H )-he

3- (1- (4-Amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-b] pyrimidin-1-yl) ethyl) -8-fluoro-2phenylisoquinolin-1 (2H )-he

The title compound as a brown solid (0.025 g, 13%) was obtained using a method similar to that described in Example 1, from 3- (3-fluoro-4-isopropoxyphenyl) -1N pyrazolo [3,4-b ] pyrimidine-4-amine ^! (0.099 g, 0.346 mmol), DMF (2.2 ml), potassium carbonate (0.096 g, 0.693 mmol) and intermediate 4 (0.156 g, 0.519 mmol). T _pl : 264-266 ° C. Mass: 553.1 (M ++ 1).

Example 3

2- (1 - (4-Amino-3 - (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-b] pyrimidin-1-yl) ethyl) -5-fluoro-3 phenylquinazolin-4 ( 3H) -one

2- (1 - (4-Amino-3 - (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-b] pyrimidin-1-yl) ethyl) -5-fluoro-3 phenylquinazolin-4 ( 3H) -one

The title compound as a brown solid (0.050 g, 26%) was obtained using a method similar to that described in Example 1, from 3- (3-fluoro-4-isopropoxyphenyl) -1N pyrazolo [3,4-b ] pyrimidine-4-amine ^! (0.099 g, 0.346 mmol), DMF (2.2 ml), potassium carbonate (0.096 g, 0.693 mmol) and intermediate 6 (0.157 g, 0.519 mmol). T _pl : 251-153 ° C. Mass: 553.8 (M +).

Example 4

2- (1- (4-Amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-b] pyrimidin-1-yl) ethyl) -6-fluoro-3phenylquinazolin-4 (3H )-he

2- (1- (4-Amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-b] pyrimidin-1-yl) ethyl) -6-fluoro-3phenylquinazolin-4 (3H )-he

The title compound as a brown solid (0.080 g, 42%) was obtained.

- 34 029614

using a method similar to that described in example 1, from 3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4th] pyrimidin-4-amine ¹ (0.099 g, 0.346 mmol), DMF ( 2.2 ml), potassium carbonate (0.096 g, 0.693 mmol) and intermediate 8 (0.210 g, 0.693 mmol). T _pl : 215-218 ° C. Mass: 553.9 (M +).

Example 5

3- (1 - (4-Amino-3 - (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4th] pyrimidin-1-yl) ethyl) -2phenylisoquinolin-1 (2H) -one

3- (1 - (4-Amino-3 - (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4th] pyrimidin-1-yl) ethyl) -2phenylisoquinolin-1 (2H) -one

The title compound as a whitish solid (0.109 g, 39%) was obtained using a method similar to that described in Example 1, from 3- (3-fluoro-4-isopropoxyphenyl) -1N-pyrazolo [3,4-th ] pyrimidine-4-amine ^! (0.150 g, 0.522 mmol), DMF (3.5 ml), potassium carbonate (0.144 g, 1.044 mmol) and intermediate 9 (0.296 g, 1.044 mmol). T _pl : 264-267 ° C. Mass: 555.0 (M +).

Examples 5a and 5b

(+) - 3- (1- (4-Amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-th] pyrimidin-1-yl) ethyl) -2-phenylisoquinolin-1 (2H) -one

and (-) - 3 - (1 - (4-amino-3 - (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4th] pyrimidin-1 -yl) ethyl) -2-phenylisoquinoline- 1 (2H) -one

Two enantiomerically pure isomers were separated from 3- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4th] pyrimidin-1-yl) ethyl) -2-phenylisoquinolin-1 (2H) -one (0.500 g) under preparative 8PC conditions on a ΟΗΙΚΑΡΡΑΚ Αδ-H column (250x20 mm; 5 μm) using methanol: CO ₂ (40:60) as the mobile phase, consumption of 80 g / min.

Example 5a Brown solid (0.438 g), e. 100%. Κί: 2.29 min. Mass: 535.2 (M +). T _pl :

231–233 ° C.

Example 5b. Brown solid (0.439 g), e. 100%. Κί: 3.99 min. Mass: 535.2 (M +). T _pl :

232-235 ° C.

Example 6

2- (1 - (4-Amino-3 - (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4th] pyrimidin-1-yl) ethyl) -3-phenylquinazolin-4 (3H) - he

2- (1 - (4-Amino-3 - (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4th] pyrimidin-1-yl) ethyl) -3-phenylquinazolin-4 (3H) - he

The title compound as a brown solid (0.200 g, 64%) was obtained using a method similar to that described in Example 1, from 3- (3-fluoro-4-isopropoxyphenyl) -1N pyrazolo [3,4 th ] pyrimidine-4-amine ^! (0.168 g, 0.584 mmol), DMF (2.0 ml), potassium carbonate (0.121 g, 0.877 mmol) and intermediate 11 (0.248 g, 0.877 mmol). _Mp: 236-239 ° C. Mass: 536.1 (M +).

Examples 6a and 6b

(+) - 2- (1- (4-Amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-th] pyrimidin-1-yl) ethyl) -3phenylquinazolin-4 (3H )-he

and (-) - 2- (1 - (4-amino-3 - (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-th] pyrimidin-1-yl) ethyl) -3 phenylquinazolin-4 (3H) -one

Two enantiomerically pure isomers were separated from 2- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-th] pyrimidin-1-yl) ethyl) -3-phenylquinazolin-4 (3H) -one (0.500 g) under preparative 8PC conditions on a ΡΠΙΡΑΕΡΑΚ Αδ-H column (250x20 mm; 5 μm) using methanol: CO ₂ mixture (55:45) as a mobile phase, flow rate 60 g / min.

Example 6a Brown solid (0.519 g), e. 100%. Κί: 2.41 min. Mass: 536.2 (M +). T _pl : 189-192 ° C.

Example 6b. Brown solid (0.490 g), e. 99.62%. Κί: 4.10 min. Mass: 536.2 (M +). T _pl : 192-195 ° C.

Example 7

3- (1 - (4-Amino-3 - (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3,4-th] pyrimidine-1 -yl) ethyl) -2-phenylisoquinolin-1 (2H) - he

3- (1 - (4-Amino-3 - (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3,4-th] pyrimidine-1 -yl) ethyl) -2-phenylisoquinolin-1 (2H) - he

To the compound according to example 5 (0.060 g, 0.112 mmol) in dichloromethane (10 ml), cooled to 0 ° C, boron tribromide (1M in dichloromethane, 0.64 ml) was added dropwise and stirred for 1 h. The reaction was quenched with 2N. HC1 solution, the mixture was extracted with dichloromethane, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography using ethyl acetate: petroleum ether to afford the title compound as an off-white solid (0.025 g, 45%). _Mp : 237-239 ° C. Mass: 492.8 (M +).

Examples 7a and 7b

(+) - 3 - (1 - (4-Amino-3 - (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3,4th] pyrimidin-1-yl) ethyl) -2-phenylisoquinolin-1 (2H) -one

- 35 029614

and (-) - 3- (1- (4-amino-3- (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3,4th] pyrimidin-1-yl) ethyl) -2-phenylisoquinol in -1 (2H) -one

Two enantiomerically pure isomers were separated from 3- (1- (4-amino-3- (3-fluoro-4-hydroxyphenyl) -1 -Npyrazolo [3,4-th] pyrimidin-1-yl) ethyl) -2-phenylisoquinolin-1 (2H) -one (0.500 g) in a preparative column 8RS SSHKLRLK Αδ-H (250x20 mm, 5 micron) using methanol: CO ₂ (55:45) as the mobile phase, flow rate 60 g / min.

Example 7a Brown solid (0,428 g), e. 100%. Κΐ: 2.25 min. Mass: 493.2 (M +). T _pl :

229-231 ° C.

Example 7b. Brown solid (0.347 g), e. 99.48%. Κΐ: 4.11 min. Mass: 493.2 (M +). T _pl :

230-223 ° C.

Example 8

2- (1 - (4-Amino-3 - (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3,4-th] pyrimidin-1 -yl) ethyl) -3-phenylquinazoline-4 (3H) - he

2- (1 - (4-Amino-3 - (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3,4-th] pyrimidin-1 -yl) ethyl) -3-phenylquinazoline-4 (3H) - he

The title compound as a brown solid (0.035 g, 40%) was obtained using a method analogous to that described in example 7, from the compound according to example 6 (0.095 g, 0.177 mmol), dichloromethane (5.0 ml) and boron tribromide (1M in dichloromethane, 1.0 ml). _Mp: 230233 ° C. Mass: 494.1 (M ++ 1).

Example 9

X (5- (4-Amino-1- (1- (1 -oxo-2-phenyl-1,2-dihydroisoquinolin-3 -yl) ethyl) -1H-pyrazolo [3,4-th] pyrimidine-3- yl) -2-methoxyphenyl) methanesulfonamide

^ (5- (4-amino-1- (1- (1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl) ethyl) -1H-pyrazolo [3,4-th] pyrimidine-3- (yl) -2-methoxyphenyl) methanesulfonamide: To a solution of intermediate 12 (0.200 g, 0.393 mmol) in DME (2 ml) and water (0.7 ml) was added ^ (2-methoxy-5- (4,4,5 , 5-tetramethyl-1,3,2-dioxaboran-2-yl) phenyl) methanesulfonamide ² (0.157 g, 0.590 mmol) and sodium carbonate (0.083 g, 0.786 mmol) and the system was degassed for 5 minutes and bis- [[ (diphenylphosphino) ferrocene] dichloropalladium (ΙΙ) (0.064 g, 0.078 mmol) under a nitrogen atmosphere and the mixture was heated to 100 ° C in a microwave reactor for 15 minutes. The reaction mixture was filtered through Celite, diluted with ethyl acetate, dried over Ν; · ι ₂ 8Θ. · Ι, and concentrated. The crude product was purified by column chromatography using ethyl acetate: petroleum ether to obtain the target compound as a brown solid (0.033 g, 15%). T _pl : 260-263 ° C. Mass: 582.1 (M ++ 1).

Examples 9a and 9b

(+) - ^ (5- (4-Amino-1- (1- (1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl) ethyl) -1H-pyrazolo [3,4th] pyrimidin-3-yl) -2-methoxyphenyl) methanesulfonamide

and (-) ^ - (5- (4-amino-1- (1- (1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl) ethyl) -1H-pyrazolo [3,4 minutes ] pyrimidin-3-yl) -2-methoxyphenyl) methanesulfonamide

Two enantiomerically pure isomers were separated from ^ (5- (4-amino-1- (1- (1-oxo-2-phenyl-1,2-dihydroisoquinolin-3 -yl) ethyl) -1H-pyrazolo [3,4- d] pyrimidine-3-yl) -2-methoxyphenyl) -methanesulfonamide (0.500 g) under preparative 8PC on a CΗIΚL ^ ΡLΚ Αδ-H column (250x20 mm; 5 μm) using methanol: CO ₂ (40:60) as a mobile phase, consumption of 60 g / min.

Example 9a Brown solid (0.149 g), e. 99.55%. Κΐ: 2.06 min. Mass: 582.2 (M +). T _pl : 165-168 ° C.

Example 9b. Brown solid (0,212 g), e. 99.79%. Κΐ: 3.67 min. Mass: 582.2 (M +). T _pl : 158-162 ° C.

Example 10

2- (1 - (4-Amino-3 - (4-methoxy-3-nitrophenyl) -1H-pyrazolo [3,4-th] pyrimidin-1-yl) ethyl) -3-phenylquinazolin-4 (3H) - he

2- (1 - (4-Amino-3 - (4-methoxy-3-nitrophenyl) -1H-pyrazolo [3,4-th] pyrimidin-1-yl) ethyl) -3-phenylquinazolin-4 (3H) - he

The title compound as a brown solid (1.05 g, 70%) was obtained using a method similar to that described in Example 1, from 3- (4-methoxy-3-nitrophenyl) -1H-pyrazolo [3.4 th] pyrimidine-4-amine (0.610 g, 2.15 mmol), DMF (9.6 ml), potassium carbonate (0.594 g, 4.30 mmol) and intermediate 11 (0.800 g, 2.79 mmol) and used without purification in the next stage.

Example 11

3- (1- (4-Amino-3- (3-amino-4-methoxyphenyl) -1H-pyrazolo [3,4-th] pyrimidin-1-yl) ethyl) -2-phenylisoquinolin-1 (2H) - he

3- (1 - (4-Amino-3 - (3-amino-4-methoxyphenyl) -1H-pyrazolo [3,4th] pyrimidin-1-yl) ethyl) -2-phenylisoquinolin-1 (2H) - he

To a solution of the compound according to Example 10 (1.00 g, 1.98 mmol) in ethanol (20 ml) was added Νί Pe- 36 029614

ney (0.50 g) and hydrogenated at 40 ρδί for 12 hours. The reaction mixture was passed through a pad with celite and concentrated. The crude product was purified by column chromatography using ethyl acetate: petroleum ether to give the final product as a yellow solid (0.54 g, 57%), which was used without purification in the next step.

Example 12

N- (5- (4-Amino-1- (1- (4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl) -1H-pyrazolo [3,4-4] pyrimidine-3 -yl) -2-methoxyphenyl) methanesulfonamide

N- (5- (4-Amino-1- (1- (4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl) -1H-pyrazolo [3,4-4] pyrimidine-3 -yl) -2-methoxyphenyl) methanesulfonamide

Pyridine (0.08 ml, 1.03 mmol) was added to a solution of the compound according to Example 11 (0.260 g, 0.515 mmol) in dichloromethane, cooled to 0 ° C, and stirred for 10 minutes. Methanesulfonyl chloride (0.039 ml, 0.515 mmol) was added and stirred for 30 minutes. The reaction was quenched with water, the mixture was extracted with dichloromethane and dried over sodium sulfate. The crude product was purified by column chromatography using methanol: dichloromethane to give the title compound as a yellow solid (0.080 g, 26%). Mass: 583.0 (M +).

Example 13

2- (1 - (4-Amino-3 - (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3.4-4] pyrimidin-1 -yl) ethyl) -6-fluoro-3 phenylquinazolin-4 ( 3H) -one

2- (1 - (4-Amino-3 - (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3.4-4] pyrimidin-1 -yl) ethyl) -6-fluoro-3 phenylquinazolin-4 ( 3H) -one

The title compound as a yellow solid (0.026 g, 14%) was obtained using a method similar to that described in Example 7, from the compound according to Example 4 (0.200 g, 0.360 mmol), dichloromethane (10.0 ml) and boron tribromide (1M in dichloromethane, 2.05 ml). T _pl : 231-232 ° C. Mass: 511.8 (M +).

Example 14

3- (1 - (4-Amino-3 - (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3.4-4] pyrimidine-1 -yl) ethyl) -8-chloro-2phenylisoquinolin-1 (2H )-he

3- (1 - (4-Amino-3 - (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3.4-4] pyrimidine-1 -yl) ethyl) -8-chloro-2phenylisoquinolin-1 (2H ) -one: The title compound as a yellow solid (0.032 g, 29%) was obtained using a method similar to that described in example 7, from the compound according to example 1 (0.120 g, 0.210 mmol), dichloromethane (6 , 0 ml) and boron tribromide (1M in dichloromethane, 1.18 ml). T _pl : 218-219 ° C. Mass: 526.6 (M +).

Examples 14a and 14b

(+) - 3- (1- (4-Amino-3- (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3.4-4] pyrimidin-1-yl) ethyl) -8-chloro-2phenylisoquinoline -1 (2H) -one

and (-) - 3- (1- (4-amino-3- (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3.4-4] pyrimidin-1-yl) ethyl) -8-chloro 2phenylisoquinoline-1 (2H) -one

The two enantiomerically pure isomers were separated from 3- (1- (4-amino-3- (3-fluoro-4-hydroxyphenyl) -1N-pyrazolo [3.4-4] pyrimidin-1-yl) ethyl) -8-chloro-2 -phenylisoquinolin-1 (2H) -one (0.500 g) under the conditions of preparative section on a SNTKARRAK Άδ-H column (250x20 mm; 5 μm) using methanol: CO ₂ (45:55) as a mobile phase, consumption 80 g / min.

Example 14a Brown solid (0.349 g), e. 97.07%. Κί: 2.51 min. Mass: 527.1 (M +). Mp: 215-219 ° C.

Example 14b. Brown solid (0.026 g), e. 95.21%. Κ1: 3.82 min. Mass: 527.1 (M +). Mp: 215-219 ° C.

Example 15

3- (1 - (4-Amino-3 - (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3.4-4] pyrimidin-1 -yl) ethyl) -8-fluoro-2phenylisoquinolin-1 (2H )-he

3- (1 - (4-Amino-3 - (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3.4-4] pyrimidin-1 -yl) ethyl) -8-fluoro-2phenylisoquinolin-1 (2H )-he

The title compound as a yellow solid (0.066 g, 47%) was obtained using a method analogous to that described in example 7, from the compound according to example 2 (0.150 g, 0.271 mmol), dichloromethane (7.5 ml) and boron tribromide (1M in dichloromethane, 1.55 ml). _Mp : 228-229 ° C. Mass: 511.0 (M +).

Examples 15a and 15b

(+) - 3 - (1 - (4-Amino-3 - (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3.4-4] pyrimidin-1-yl) ethyl) -8-fluoro-2phenylisoquinoline -1 (2H) -one

and (-) - 3- (1- (4-amino-3- (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3.4-4] pyrimidin-1-yl) ethyl) -8-fluoro- 2phenylisoquinoline-1 (2H) -one

The two enantiomerically pure isomers were separated from 3- (1- (4-amino-3- (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3.4-4] pyrimidin-1-yl) ethyl) -8-fluoro -2-phenylisoquinolin-1 (2H) -one (0.500 g) under preparation conditions - 37 029614

tive §RS column SN1KARRAK Άδ-Η (250 x 20 mm, 5 micron) using methanol: CO ₂ (45:55) as the mobile phase, flow rate 80 g / min.

Example 15a Whitish solid (0.480 g), e. 100%. Κί: 2.91 min. Mass: 511.1 (M +). T _pl : 268-270 ° C.

Example 15b. Whitish solid (0.453 g), e. 99.9%. Κί: 5.12 min. Mass: 511.1 (M +). T _pl : 258-260 ° C.

Example 16

2- (1 - (4-Amino-3 - (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3,4-b] pyrimidin-1 -yl) ethyl) -5-fluoro-3 phenylquinazolin-4 ( 3H) -one

2- (1 - (4-Amino-3 - (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3,4-b] pyrimidin-1 -yl) ethyl) -5-fluoro-3 phenylquinazolin-4 ( 3H) -one

The title compound as a brown solid (0.050 g, 27%) was obtained using a method similar to that described in example 7, from the compound according to example 3 (0.200 g, 0.360 mmol), dichloromethane (10.0 ml) and boron tribromide (1M in dichloromethane, 2.05 ml). _Mp: 212 214 ° C. Mass: 512.0 (M +).

Examples 16a and 16b

(+) - 2- (1 - (4-Amino-3 - (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3,4-b] pyrimidin-1-yl) ethyl) -5-fluoro-3 Phenylquinazolin-4 (3H) -one

and (-) - 2- (1- (4-amino-3- (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3,4-b] pyrimidin-1-yl) ethyl) -5-fluoro- 3phenylquinazolin-4 (3H) -one

The two enantiomerically pure isomers were separated from 2- (1- (4-amino-3- (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3,4-b] pyrimidin-1-yl) ethyl) -5-fluoro-3 -phenylquinazolin-4 (3H) -one (0.500 g) under preparative 8PC on a CH1KARRAK РАδ-Η column (250 x 20 mm; 5 μm) using methanol: CO ₂ (45:55) as the mobile phase, consumption 80 g / min.

Example 16a Whitish solid (0,458 g), e. 99.88%. Κί: 2.34 min. Mass: 512.2 (M +). T _pl :

268-270 ° C.

Example 16b. Whitish solid (0.469 g), ee. 99.05%. Κί: 3.92 min. Mass: 512.2 (M +). T _pl :

269-271 ° C.

Example 17

3- (1 - (4-Amino-3 - (4- (difluoromethoxy) -3-fluorophenyl) -1H-pyrazolo [3,4-b] pyrimidin-1 -yl) ethyl) -8chloro-2-phenylisoquinolin-1 (2H) -one

3- (1 - (4-Amino-3 - (4- (difluoromethoxy) -3-fluorophenyl) -1H-pyrazolo [3,4-b] pyrimidin-1 -yl) ethyl) -8chloro-2-phenylisoquinolin-1 (2H) -one: The title compound as an off-white solid (0.020 g, 7%) was obtained using a method similar to that described in Example 1, from 3- (4 (difluoromethoxy) -3-fluorophenyl) - 1H-pyrazolo [3,4-b] pyrimidin-4-amine ¹ (0.150 g, 0.507 mmol), DMF (1.5 ml), potassium carbonate (0.140 g, 1.015 mmol) and intermediate 2 (0.323 g, 1.015 mmol). T _pl : 160-162 ° C. Mass: 576.7 (M +).

Examples 17a and 17b

(+) - 3 - (1 - (4-Amino-3 - (4- (difluoromethoxy) -3-fluorophenyl) -1H-pyrazolo [3,4-b] pyrimidin-1-yl) ethyl) -8chlor-2 -phenylisoquinolin-1 (2H) -one

and (-) - 3- (1- (4-amino-3- (4- (difluoromethoxy) -3-fluorophenyl) -1H-pyrazolo [3,4-b] pyrimidin-1-yl) ethyl) 8-chloro -2-phenylisoquinoline-1 (2H) -one

The two enantiomerically pure isomers were separated from 3- (1- (4-amino-3- (4- (difluoromethoxy) -3-fluorophenyl) 1H-pyrazolo [3,4-b] pyrimidin-1-yl) ethyl) -8- chlorine-2-phenylisoquinolin-1 (2H) -one (0.500 g) under preparative δΡC on a CH1KARRAK Άδ-H column (250x20 mm; 5 μm) using methanol: CO ₂ (50:50) as the mobile phase, consumption of 70 g / min.

Example 17a. Brown solid (0,500 g), e. 99.25%. Κί: 2.35 min. Mass: 577.2 (M +). Mp: 180-184 ° C.

Example 17b. Brown solid (0,422 g), e. 100%. Κί: 3.87 min. Mass: 577.2 (M +). T _pl : 181-185 ° C.

Example 18

3- (1- (4-Amino-3- (4-methoxy-3-nitrophenyl) -1H-pyrazolo [3,4-b] pyrimidin-1-yl) ethyl) -8-chloro-2phenylisoquinolin-1 (2H )-he

3- (1 - (4-Amino-3 - (4-methoxy-3-nitrophenyl) -1H-pyrazolo [3,4-b] pyrimidin-1-yl) ethyl) -8-chloro-2phenylisoquinolin-1 (2H )-he

The title compound as a brown solid (0.270 g, 54%) was obtained using a method similar to that described in Example 1, from 3- (4-methoxy-3-nitrophenyl) -1H-pyrazolo [3,4-b ] pyrimidine-4-amine (0.250 g, 0.846 mmol), DMF (2.5 ml), potassium carbonate (0.241 g, 1.75 mmol) and intermediate 2 (0.557 g, 1.75 mmol) and used without purification in the next stage.

- 38 029614

Example 19

3- (1 - (4-Amino-3 - (3-amino-4-methoxyphenyl) -1H-pyrazolo [3,4-b] pyrimidin-1-yl) ethyl) -8-chloro-2phenylisoquinolin-1 (2H )-he

3- (1 - (4-Amino-3 - (3-amino-4-methoxyphenyl) -1H-pyrazolo [3,4-b] pyrimidin-1-yl) ethyl) -8-chloro-2phenylisoquinolin-1 (2H )-he

The title compound as a brown solid (0.150 g, 58%) was obtained using a method analogous to that described in example 11, from the compound according to example 18 (0.270 g, 0.476 mmol), ethanol (5 ml), Raney (0,135 g) and used without purification in the next stage.

Example 20

^ (5- (4-Amino-1- (1- (8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl) ethyl) -1H-pyrazolo [3.4b] pyrimidine 3-yl) -2-methoxyphenyl) methanesulfonamide

^ (5- (4-Amino-1- (1- (8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolium-3-yl) ethyl) -1H-pyrazolo [3.4b] pyrimidine 3-yl) -2-methoxyphenyl) methanesulfonamide: The title compound as an off-white solid (0.020 g, 13%) was obtained using a method similar to that described in example 12, from the compound according to example 19 (0.135 g, 0.251 mmol), pyridine (0.10 ml, 0.484 mmol), dichloromethane (2 ml) and methanesulfonyl chloride (0.10 ml, 0.252 mmol). Mass: 616.0 (M +).

Examples 20a and 20b

(+) - ^ (5- (4-Amino-1- (1- (8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl) ethyl) -1H-pyrazolo [3, 4-b] pyrimidine-3 -yl) -2-methoxyphenyl) meta-sulfoiamide

and (-) - N- (5- (4-amino-1- (1- (8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl) ethyl) -1H-pyrazolo [ 3,4-b] pyrimidine-3 -yl) -2-methoxyphenyl) meta-sulfoiamide

Two enantiomerically pure isomers were separated from N- (5- (4-amino-1- (1- (8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl) ethyl) -1H-pyrazolo [3 , 4-b] pyrimidin-3-yl) -2-methoxyphenyl) methanesulfonamide (0.500 g) under preparative garnet pulsation on a USCARAΆ -δ-Η column (250x20 mm; 5 μm) using methanol: CO ₂ (45:55 ) as a mobile phase, consumption of 80 g / min.

Example 20a: brown solid (0.397 g), e. 98.54%. K1: 2.26 min. Mass: 616.2 (M +). T _pl : 178-18 ° C.

Example 20b: Brown solid (0.252 g) e.e. 98.77%. K1: 3.18 min. Mass: 616.2 (M +). Mp: 180-183 ° C.

Example 21

3- (1- (4-Amino-3- (3-methyl-1H-indazol-6-yl) -1H-pyrazolo [3,4-b] pyrimidin-1-yl) ethyl) -8-chloro-2-phenylisoquinoline -1 (2H) -one

3- (1- (4-Amino-3- (3-methyl-1H-indazol-6-yl) -1H-pyrazolo [3,4-b] pyrimidin-1-yl) ethyl) -8-chloro-2-phenylisoquinoline -1 (2H) -one: The title compound as a brown solid (0.020 g, 10%) was obtained using a method similar to that described in Example 9, from intermediate 13 (0.200 g, 0.368 mmol), DME (2.5 ml), water (1.0 ml), tert-butyl-3-methyl-6- (4,4,5,5 tetramethyl-1,3,2-dioxaboran-2-yl) -1H- indazole-1-carboxylate (0.198 g, 0.552 mmol), sodium carbonate (0.078 g, 0.736 mmol) and bis - [(diphenylphosphino) ferrocene] dichloropalladium (II) (0.060 g, 0.073 mmol) under microwave irradiation (Microwave irradiation power = 100 W, temperature = 100 ° C) for 45 min. T _pl : 289-291 ° C. Mass: 546.9 (M +).

Examples 21a and 21b

(+) - 3- (1- (4-Amino-3- (3-methyl-1H-indazol-6-yl) -1H-pyrazolo [3,4-b] pyrimidin-1-yl) ethyl) -8 -chloro-2phenylisoquinolin-1 (2H) -one

and (-) - 3 - (1 - (4-amino-3 - (3-methyl-1H-indazol-6-yl) -1H-pyrazolo [3,4-b] pyrimidin-1 -yl) ethyl) - 8-chloro-2-phenylisoquinolin-1 (2H) -one

Two enantiomerically pure isomers were separated from 3- (1- (4-amino-3- (3-methyl-1H-indazol-6-yl) -1H pyrazolo [3,4-b] pyrimidin-1-yl) ethyl) -8 -chloro-2-phenylisoquinolin-1 (2H) -one (0.500 g) under preparative δΡC conditions on a USCA РАδ-H column (250x20 mm; 5 μm) using methanol: CO ₂ (35:65) as the mobile phase consumption 80 g / min.

Example 21a Brown solid (0.327 g), e. 98.29%. K1: 4.26 min. Mass: 547.2 (M +). Mp: 230-233 ° C.

Example 21b. Brown solid (0.599 g), e. 95.03%. K1: 5.44 min. Mass: 547.2 (M +). Mp: 225-227 ° C.

Example 22

2- {1- [4-Amino-3- (3-fluoro-4-isopropoxyphenyl) pyrazolo [3,4-b] pyrimidin-1-yl] propyl} -3-phenyl3H-quinazolin-4-one

2- {1- [4-Amino-3- (3-fluoro-4-isopropoxyphenyl) pyrazolo [3,4-b] pyrimidin-1-yl] propyl} -3-phenylZN-quinazolin-4-one

To a solution of 3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-b] pyrimidine-4-amine ¹ (0.115 g, 0.402 mmol) in DMF (2 ml) was added potassium carbonate (0.084 g, 0,604 mmol) and stirred at room temperature

- 39 029614

temperature for 30 min. Intermediate 15 (0.180 g, 0.604 mmol) was added and stirred at 90 ° C for 12 h. The reaction was quenched with water and the precipitate was filtered off and dried in vacuo. The crude product was purified by column chromatography using methanol: dichloromethane to give the title compound as a brown solid (0.070 g, 17%). T _{1 |; |} : 261-263 ° C. Mass: 550.6 (M ++ 1).

Biological research

Pharmacological properties of the compounds according to the present invention can be confirmed using various pharmacological studies. Pharmacological studies that can be performed using the compounds according to the present invention and / or their pharmaceutically acceptable salts, are listed below.

Study 1. Fluorescence determination of the activity of the enzyme ΡI3-kinase

Phosphoinositide 3-kinases (ΡΙ3Κ) belong to the class of lipid kinases, which play an important role in the regulation of several key cellular processes. ΡΙ3Κ is able to phosphorylate phosphoinositols by hydroxyl in position 3, due to which secondary messengers are produced that are involved in the underlying signaling phenomena. The study of homogeneous fluorescence with time resolution (NTCR) provides for the detection of 3,4,5-triphosphate (3) obtained by phosphorylation of phosphatidyl inositol-4,5-biphosphate (ΡΙΡ2) under the influence of о3ΡΙ isoforms, such as α, β, γ or δ .

The activity of α, β, γ, or δ ΡΙ3 из isoforms should be determined using the Н3Κ human NTKR ™ assay kit (MPNroh, Vsepsa, MA) with modifications. Incubation in all cases was carried out at room temperature. Briefly, 0.5 μl of 40X inhibitor (in 100% DMSO) or 100% DMSO was added to each well of a 384-well black plate (Ogeteg Vu-Ope, Mopgoi,) containing 14.5 μl of reaction buffer / Ρ ^ mixture ( 10 mM MDCl ₂ , 5 mM ETT, 1.38 μM (2), containing or not containing the enzyme, and incubated for 10 min. After the initial incubation, 5 μl / well of 400 μM ATP was added and incubated for another 30 minutes. The reaction was stopped by adding 5 μl / well of a stopping solution (MPNrog, VShepsa, MA). Then, five microliters of the detection mixture (MPNroh, Vsepsa, MA) were added to each well and incubated for 6-18 hours without access of light. The NTKR ratio was measured on a microplate analysis device (WMO LA, HEM) at an excitation wavelength of 337 nm and emission wavelengths of 665 and 620 nm, the integration time was 400 μs. The data were analyzed using OgarPnPqt (OgarPnP software; 8e Ehedo, CA, to determine; ₀ ). The% inhibition values for α, β, γ or δ о3Κ isoforms for the compounds according to the present invention are as follows: _

Example inhibition,% @ R13k6 Р13к "/ P13ka R13kr 100/300 nM 1С50 100/300 nM 1С50 1 μM 1 μM one ϋ - E - E1 E1 2 3 four five 5a 5b 6 6a 6b 7 7a 7b eight 9 9a 9b 12 13 14 14a 14b 15 15a 15b sixteen 16a 16b 17 E E E BUT BUT WITH BUT BUT ϋ WITH AT WITH ϋ with BUT WITH E ϋ AT BUT AT WITH BUT ϋ WITH BUT ϋ BUT 3.05 2.74 13.33 16.22 4.2 9.99 33.26 E E WITH AT AT E WITH WITH E ϋ AT ϋ E ϋ WITH E ϋ ϋ BUT BUT ϋ WITH WITH E WITH ϋ E BUT 22.18 15.01 57.73 203.3 19.54 52.04 121.6 E1 E1 E1 E1 E1 E1 E1 E1 E1 E2 E1 E1 E1 ϋ E1 E1 E1 E1 ϋ E1 E1 E1 E1 E1 E1 E1 E1 ϋ E2 E2 ϋ E2 ϋ AT E1 ϋ ϋ ϋ ϋ ϋ ϋ WITH ϋ Ε2 ϋ Ε2 Β Ε2 ϋ ϋ Ε2 Ε1 Β Ε2 Ε1 WITH 17a ϋ - E - E1 Ε1 17b BUT 45.61 BUT 47.26 E1 ϋ 20 BUT AT WITH ϋ 20a AT 76.41 ϋ 141.6 E1 Ε2 20b ϋ - E - E1 ϋ 21 BUT - AT - ϋ Β 21a BUT - AT - E1 Ε1 21b BUT - WITH - E1 Ε2

the underlined values correspond to compounds tested at 300 nM; inhibition,%: A corresponds to> 80- <100%; B corresponds to> 60- <80%; C corresponds to> 40- <60%; I) corresponds to> 20- <40%, E corresponds to 0- <20%, E2 corresponds to> 10- <20%, and E1 corresponds to 0- <10%.

- 40 029614

Although the invention is described herein with reference to specific embodiments, it should be understood that these embodiments only illustrate the principles and methods of applying the present invention. Thus, it should be understood that numerous modifications of the illustrative implementation options are possible, as well as other schemes can be proposed without departing from the spirit and scope of the present invention described above. It is assumed that the attached

Claims (18)

The claims define the scope of the invention, and methods and structures that are not beyond the scope of said claims and equivalents of claims are covered by said claims. All publications and patents and / or patent applications cited in that application are incorporated into this application by reference to the same extent as if it were specifically and individually indicated that the content of each individual publication or patent application is included in present application by reference. CLAIM 1. The compound of formula (ΕΆ) or its pharmaceutically acceptable salt, where in each case, K ^{1 is} independently H, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _2-10 alkenyl, substituted or unsubstituted C _2-12 alkynyl, or halogen; in each case, K is independently H, substituted or unsubstituted C _1-8 alkyl or halogen; K ^a is substituted or unsubstituted C _1-8 alkyl; K ^{b is} independently selected from H and substituted or unsubstituted C _1-8 alkyl; K ^c is H, substituted or unsubstituted C _1-8 alkyl, -IN ₂ or halogen; in each case, η is independently selected from 0, 1, 2, 3, or 4, and Su is chosen from Where 2 3 K and K are independently selected from H, halogen, hydroxyl, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _1-8 alkoxy, SI, -IN-8O ₂ -K ', -IO ₂ , -IN ₂ , - IN-C (O) -K ', -C (O) IN-K', -8O ₂ -K 'or -8O ₂ IC'K'; K 'is selected from H, hydroxy, halogen, carboxyl, cyano, nitro, oxo (= O), thio (= 8), substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _1-8 alkoxy, substituted or unsubstituted C _2-10 alkenyl, substituted or unsubstituted C _2-12 alkynyl, substituted or unsubstituted C _3-12 cycloalkyl, substituted or unsubstituted C _3-8 cycloalkenyl, substituted or unsubstituted C3-8 cycloalkylalkyl, substituted or unsubstituted C3-8 cycloalkenylalkyl, substituted or unsubstituted 3-15 membered heterocyclyl, substituted or unsubstituted about 3-15 membered heterocyclylalkyl, substituted or unsubstituted C _6-20 aryl, substituted or unsubstituted C _6-20 arylalkyl, substituted or unsubstituted 5-14 membered heteroaryl containing one or more heteroatoms selected from Ν, O and 8, and substituted or unsubstituted 5-14 membered heteroarylalkyl containing one or more heteroatoms selected from, O, and 8; K ⁴ is H or substituted or unsubstituted C _1-8 alkyl, wherein “substituted” in the definitions above refers to substitution by any one of the following substituents or any combination thereof, where the substituents may be the same or different and - 41 029614 independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (= O), thio (= 8), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or ne substituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, substituted or unsubstituted guanidine, -OOC ^x , -C (O) K ^x , -C (8) K ^x , -C (O) NK ^x K ^y , -C (O) OCC ^x K ^y , -MM -M'SOMM -Ν (Κ ^Χ ) 8ΘΚ \ -Ν (Κ ^χ ) 8Θ2Κ \ - (= Ν-Ν (Κ ^Χ ) ΚΥ -MOMY -M ΑΜΜίΟΜΜ ΜΊΜΜί 8ιΙΜ ΜΊΜίΜΜΊΜΜ -8 (ΜΊΜΜ, -8O2NK ^x K ^y -, -OK ^x , -OK ^x S (o) MK ^y K ² , -OK ^x S (O) OK ^y -, -OS (O) K ^x , -OC (O) MK ^x K ^y , -K ^x MK ^y C (O) K ² , -K ^x OK ^y , -K ^x C (O) OK ^y , -K ^x C (o) MK ^y K ² , -K ^x C (o) k ^x , -K ^x OC (O) K ^y , -8K ^x , -8OK ^x , -8O2K ^x and -ΘΝΘ2, where K ^x , K ^y and K ² in each of the above groups can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted quinil, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, s substituted or unsubstituted heterocyclic ring or substituted heterocyclylalkyl ring, or any two of K ^x , K ^y and K ² may be combined to form a substituted or unsubstituted saturated or unsaturated 310-membered ring, which may contain heteroatoms, which may be the same or different and selected from O, ΝΚ ^Χ , where K ^x is hydrogen or C 1-8 alkyl, or 8; however, these substituents in the above substituted groups cannot be additionally substituted. 2. The compound of formula (Ι-B) or its pharmaceutically acceptable salt, where К ¹ , К, К ^а , К ^ь , К ^с , Су, К ² , К ³ , К ⁴ and К 'are as defined in item 1. 3. The compound of the formulas (Ι-Α1), (Ι-Α2), (Ι-Α3), (Ι- Α4), (Ι-Α5), (Ι-β1), (EB2), (Ι-RE), C-B4) or (Ι-β5) - 42 029614 or its pharmaceutically acceptable salt, where K ¹ , K, K ^a , K ^b , K ^with and Su such as defined in claim 1. 4. The compound of formula (II) - 4З 029614 or its pharmaceutically acceptable salt, where X represents CH or Ν; and K ¹ , K, K ^a , K ^b , p, K ² , K ³ , K ^with and Su such as defined in paragraph 1. 5. Compound of formula (ΙΙ-1), (ΙΙ-2), (ΙΙ-З), (ΙΙ-4) or (ΙΙ-5) (I-5) or its pharmaceutically acceptable salt, where К ¹ , К, К ^а , п, X, К ² , К ³ , К ⁴ and К ^с are as defined in item 1. 6. The compound according to any one of paragraphs.1-5, characterized in that - 44 029614 K ¹ is H or halogen; K is H or halogen; K ^with represents H; and and is 0 or 1. 7. The compound according to any one of paragraphs.1-6, characterized in that K ¹ is H, P or C1; K is P; and K ^b represents H, and To ^and represents methyl or ethyl. 8. The compound according to any one of paragraphs.1-7, characterized in that Su is selected from 9. The compound of formula (III) or its pharmaceutically acceptable salt, where K ¹ , K, K ^a , η, X, K ² , K ³ , K ^with and Su such as defined in paragraph 1. 10. The compound of formula (ΙΙΙ-Α) or (ΙΙΙ-B) η ₂ ν η ₂ ν (ΙΙΙ-Α) (ΙΙΙ-Β) or its pharmaceutically acceptable salt, where Su is selected from - 45 029614 To ^a represents methyl or ethyl; K and K ^{1 are} independently H or halogen; K ^with represents H; X is CH or Ν; and n is 0 or 1. 12. A compound selected from З- (1- (4-amino-З- (З-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [З, 4-D] pyrimidin-1-yl) ethyl) -8-chloro-2phenylisoquinolin-1 (2H )-she is; З- (1- (4-amino-З- (З-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [З, 4-D] pyrimidin-1-yl) ethyl) -8-fluoro-2phenylisoquinolin-1 (2H )-she is; 2- (1 - (4-amino-3 - (3-fluoro-4-isopropoxyphenyl) -1 H-pyrazolo [3,4-ά] pyrimidin-1 -yl) ethyl) -5-fluoro-3 phenylquinazoline-4 (3N) -one; 2- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3, 4-D] pyrimidin-1-yl) ethyl) -6-fluoro-3phenylquinazoline-4 (3H )-she is; 3- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3, 4-D] pyrimidin-1-yl) ethyl) -2-phenylisoquinolin-1 (2H) - she is; (+) - 3- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3, 4-D] pyrimidin-1-yl) ethyl) -2-phenylisoquinolin-1 (2H) -one; (-) - 3- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3, 4-D] pyrimidin-1-yl) ethyl) -2-phenylisoquinolin-1 (2H) -one; 2- (1 - (4-amino-3 - (3-fluoro-4-isopropoxyphenyl) -1 H-pyrazolo [3,4-ά] pyrimidine-1 -yl) ethyl) -3-phenylquinazolin-4 (3N) -she is; (+) - 2- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3, 4-d] pyrimidin-1-yl) ethyl) -3-phenylquinazolin-4 (3N) -one; (-) - 2- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3, 4-d] pyrimidin-1-yl) ethyl) -3-phenylquinazolin-4 (3N) -one; 3- (1- (4-amino-3- (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3, 4-d] pyrimidin-1-yl) ethyl) -2-phenylisoquinolin-1 (2H) - she is; (+) - 3- (1- (4-amino-3- (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3, 4-d] pyrimidin-1-yl) ethyl) -2-phenylisoquinolin-1 (2H) -one; (-) - 3- (1- (4-amino-3- (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3, 4-d] pyrimidin-1-yl) ethyl) -2-phenylisoquinolin-1 (2H) -one; 2- (1 - (4-amino-3 - (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3,4-ά] pyrimidine-1 -yl) ethyl) -3-phenylquinazolin-4 (3N) -she is; N- (5- (4-amino-1- (1- (1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl) ethyl) -1 H-pyrazolo [3,4 Schiamidin-3-yl) -2-methoxyphenyl) methanesulfonamide; (+) - ^ (5- (4-amino-1- (1- (1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl) ethyl) -1H-pyrazolo [3.4-pyrimidin-3- yl) -2-methoxyphenyl) methanesulfonamide; (-) - Ν- (5 - (4-amino-1- (1- (1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl) ethyl) -1H-pyrazolo [3,4- ά] pyrimidine-3-yl) -2-methoxyphenyl) methanesulfonamide; 2- (1- (4-amino-3- (4-methoxy-3-nitrophenyl) -1H-pyrazolo [3,4 Shpyrimidin-1-yl) ethyl) -3-phenyl- 46 029614 quinazolin-4 (3H) -one; 3- (1 - (4-amino-3 - (3-amino-4-methoxyphenyl) -1H-pyrazolo [3,4-E] pyrimidin-1-yl) ethyl) -2-phenylisoquinolin-1 (2H) - she is; Yu (5- (4-amino-1- (1- (4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl) -1H-pyrazolo [3,4-E] pyrimidin-3- yl) -2-methoxyphenyl) methanesulfonamide; 2- (1- (4-amino-3- (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3,4-E] pyrimidin-1-yl) ethyl) -6-fluoro-3-phenylquinazolin-4 (3H) -one; 3- (1- (4-amino-3 - (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3,4-E] pyrimidin-1-yl) ethyl) -8-chloro-2-phenylisoquinolin-1 (2H) -one; (+) - 3- (1- (4-amino-3 - (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3,4-E] pyrimidin-1-yl) ethyl) -8-chloro-2phenylisoquinoline -1 (2H) -one; (-) - 3 - (1 - (4-amino-3 - (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3,4-E] pyrimidin-1 -yl) ethyl) -8-chloro-2phenylisoquinoline -1 (2H) -one; 3- (1- (4-amino-3- (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3,4-E] pyrimidin-1-yl) ethyl) -8-fluoro-2-phenylisoquinolin-1 (2H) -one; (+) - 3 - (1 - (4-amino-3 - (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3,4-E] pyrimidin-1-yl) ethyl) -8-fluoro-2phenylisoquinoline -1 (2H) -one; (-) - 3 - (1 - (4-amino-3 - (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3,4-E] pyrimidin-1 -yl) ethyl) -8-fluoro-2phenylisoquinoline -1 (2H) -one; 2- (1- (4-amino-3- (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3,4-E] pyrimidin-1-yl) ethyl) -5-fluoro-3-phenylquinazolin-4 (3H) -one; (+) - 2- (1 - (4-amino-3 - (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3,4-E] pyrimidin-1-yl) ethyl) -5-fluoro-3 phenylquinazolin-4 (3H) -one; (-) - 2- (1 - (4-amino-3 - (3-fluoro-4-hydroxyphenyl) -1H-pyrazolo [3,4-E] pyrimidin-1 -yl) ethyl) -5-fluoro-3 phenylquinazolin-4 (3H) -one; 3- (1- (4-amino-3- (4- (difluoromethoxy) -3-fluorophenyl) -1H-pyrazolo [3,4-E] pyrimidin-1 -yl) ethyl) -8chlor-2-phenylisoquinolin-1 (2H) -one; (+) - 3- (1- (4-amino-3- (4- (difluoromethoxy) -3-fluorophenyl) -1H-pyrazolo [3,4-E] pyrimidin-1-yl) ethyl) -8chlor-2 phenylisoquinolin-1 (2H) -one; (-) - 3 - (1 - (4-amino-3 - (4- (difluoromethoxy) -3-fluorophenyl) -1H-pyrazolo [3,4-E] pyrimidin-1 -yl) ethyl) -8 chloro-2 phenylisoquinolin-1 (2H) -one; 3- (1 - (4-amino-3 - (4-methoxy-3-nitrophenyl) -1H-pyrazolo [3,4-E] pyrimidin-1-yl) ethyl) -8-chloro-2-phenylisoquinolin-1 (2H) -one; 3- (1 - (4-amino-3 - (3-amino-4-methoxyphenyl) -1H-pyrazolo [3,4-E] pyrimidin-1-yl) ethyl) -8-chloro-2-phenylisoquinolin-1 (2H) -one; Yu (5- (4-amino-1- (1- (8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl) ethyl) -1H-pyrazolo [3,4E] pyrimidine- 3-yl) -2-methoxyphenyl) methanesulfonamide; (+) - L- (5- (4-amino-1- (1- (8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl) ethyl) -1H-pyrazolo [3 , 4E] pyrimidin-3-yl) -2-methoxyphenyl) methanesulfonamide; (-) - L- (5- (4-amino-1- (1- (8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl) ethyl) -1H-pyrazolo [3 , 4E] pyrimidin-3-yl) -2-methoxyphenyl) methanesulfonamide; 3- (1- (4-amino-3- (3-methyl-1H-indazol-6-yl) -1H-pyrazolo [3,4-E] pyrimidin-1-yl) ethyl) -8-chloro-2 phenylisoquinolin-1 (2H) -one; (+) - 3- (1- (4-amino-3- (3-methyl-1H-indazol-6-yl) -1H-pyrazolo [3,4-E] pyrimidin-1-yl) ethyl) -8 -chloro-2phenylisoquinolin-1 (2H) -one; (-) - 3 - (1 - (4-amino-3 - (3-methyl-1H-indazol-6-yl) -1H-pyrazolo [3,4-E] pyrimidin-1 -yl) ethyl) -8 -chloro-2phenylisoquinolin-1 (2H) -one; 2- {1- [4-amino-3 - (3-fluoro-4-isopropoxyphenyl) pyrazolo [3,4-E] pyrimidin-1-yl] propyl} -3-phenyl 3H-quinazolin-4-one; and its pharmaceutically acceptable salts. 13. A pharmaceutical composition for inhibiting the catalytic activity of a ΡΙ3 kinase in a cell, containing a compound according to any one of claims 1 to 12 and a pharmaceutically acceptable carrier. 14. A method of inhibiting the catalytic activity of an ΡI3 kinase present in a cell, comprising bringing said cell into contact with an effective amount of a compound according to any one of claims 1 to 12. 15. The method according to p. 14, characterized in that said inhibition is carried out in a subject suffering from a disease or disorder, which is a cancer, a bone disorder, an inflammatory disease, an immune disease, a disease of the nervous system, a metabolic disease, a respiratory disease, a thrombosis or a disease hearts. 16. The use of a compound according to any one of claims 1 to 12 for the preparation of a medicament for the treatment of a disease, disorder or condition in which inhibition of the catalytic activity of a kinase may have a beneficial effect. - 47 029614 17. A method of treating a disease or disorder associated with "3", comprising the step of administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 12. 18. The method according to claim 17, wherein said disease, disorder or condition associated with "3" is an immune system related disease, disease or disorder, including inflammation, cancer, liver disease or disorder, or kidney disease or disorder . 19. The method of claim 17, wherein said disease, disorder or condition associated with ΡΙ3ΡΙ is selected from hematopoietic tumors of lymphoid origin, leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Berkett's lymphoma, hematopoietic tumors of myeloid origin, acute myelogenous leukemia, chronic myelogenous leukemia, myelodysplastic syndrome, promyelocytic le goat, bladder carcinoma, breast carcinoma, colon carcinoma, kidney carcinoma, liver carcinoma, lung carcinoma, small cell lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer , prostate cancer, skin cancer, squamous carcinoma, tumors of mesenchymal origin, fibrosarcoma, rhabdomyosarcoma, tumors of the central and peripheral nervous system, astrocytomas, neuroblastomas, gliomas, schwannomas, melanomas, minoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosa, aphracneopathy syndrome, follicular thyroid cancer and Kaposi's sarcoma, inflammation, glomerulonephritis, uveitis, liver disease or disorders, kidney disease or disorders, chronic obstructive pulmonary disease, rheumatic heart disease, uveitis, liver disease or disorders, kidney disease or disorders, chronic obstructive pulmonary disease, rheumatoid heart disease , osteoarthritis, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, rejection of allogeneic or xenog agrah, a graft, a graft, a disease, a graft of a disease Sjogren's syndrome, organ transplant rejection, multiple sclerosis, Guillain-Barré syndrome, autoimmune uveitis, autoimmune hemolytic anemia, pernicious anemia, autoimm unnah thrombocytopenia, temporal arteritis, antiphospholipid syndrome, vasculiditis, anephritis, aphoropathy, Wehner's granulomatosis, Behcet's disease, psoriasis, herpetiform dermatitis, vulgar pemphigus, vitiligo, Crohn's disease, colitis, ulcerative colitis, primary biliary cirrhosis, anesthesia, naturoprosis, ulcers with immune system diabetes, Graves disease, Hashimoto thyroiditis, autoimmune oophoritis and orchitis, autoimmune adrenal gland disorder, systemic lupus erythematosus, polymyositis, d ermatomyositis, ankylosing spondylitis, graft rejection, skin graft rejection, arthritis, bone diseases associated with increased bone resorption, ileitis, Barrett syndrome, adult respiratory distress syndrome, chronic obstructive respiratory tract disease, corneal dystrophy, trachoma hysteromyoma, adult traumatic respiratory distress syndrome endophthalmitis, gingivitis, periodontitis, tuberculosis, leprosy, uremic complications, nephrosis, sclerodermatitis, psoriasis, chronic demyelinating diseases of the nervous system ema, neurodegeneration, alzheis , coronary heart disease, hypercholesterolemia, atherosclerosis, preeclampsia, chronic liver failure, brain and spinal cord injury, and cancer.